US20090041670A1 - Near Infrared Fluorescent Contrast Agent And Method For Fluorescence Imaging - Google Patents
Near Infrared Fluorescent Contrast Agent And Method For Fluorescence Imaging Download PDFInfo
- Publication number
- US20090041670A1 US20090041670A1 US12/147,717 US14771708A US2009041670A1 US 20090041670 A1 US20090041670 A1 US 20090041670A1 US 14771708 A US14771708 A US 14771708A US 2009041670 A1 US2009041670 A1 US 2009041670A1
- Authority
- US
- United States
- Prior art keywords
- group
- contrast agent
- substituted
- near infrared
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002872 contrast media Substances 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title description 39
- 238000000799 fluorescence microscopy Methods 0.000 title description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 125000003118 aryl group Chemical group 0.000 claims abstract description 27
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 4
- 125000006732 (C1-C15) alkyl group Chemical group 0.000 claims abstract description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 4
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 239000002504 physiological saline solution Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 2
- 238000002059 diagnostic imaging Methods 0.000 claims 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 23
- 238000003384 imaging method Methods 0.000 abstract description 13
- 210000004204 blood vessel Anatomy 0.000 abstract description 6
- 230000035699 permeability Effects 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 28
- -1 porphyrin compound Chemical class 0.000 description 28
- 239000013078 crystal Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 230000005284 excitation Effects 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 239000000975 dye Substances 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical class [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 229940126639 Compound 33 Drugs 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 5
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940125833 compound 23 Drugs 0.000 description 5
- 229940125846 compound 25 Drugs 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 125000004964 sulfoalkyl group Chemical group 0.000 description 5
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- VUCMMJBDNXZQDJ-UHFFFAOYSA-N n-(5-phenyliminopenta-1,3-dienyl)aniline;hydrochloride Chemical compound Cl.C=1C=CC=CC=1NC=CC=CC=NC1=CC=CC=C1 VUCMMJBDNXZQDJ-UHFFFAOYSA-N 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- HUFDYAIAEFHOKI-UHFFFAOYSA-N 2,3,3-trimethylindol-1-ium-5-sulfonate Chemical compound C1=C(S(O)(=O)=O)C=C2C(C)(C)C(C)=NC2=C1 HUFDYAIAEFHOKI-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 0 [1*]C1([2*])C2=C(C([6*])=C([5*])C([4*])=C2[3*])[N+](C)=C1/C=C/C=C/C=C/C=C1/N(C)C2=C(C([9*])=C([10*])C([11*])=C2[12*])C1([7*])[8*] Chemical compound [1*]C1([2*])C2=C(C([6*])=C([5*])C([4*])=C2[3*])[N+](C)=C1/C=C/C=C/C=C/C=C1/N(C)C2=C(C([9*])=C([10*])C([11*])=C2[12*])C1([7*])[8*] 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 238000002428 photodynamic therapy Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- AIGNCQCMONAWOL-UHFFFAOYSA-N 1,3-benzoselenazole Chemical group C1=CC=C2[se]C=NC2=C1 AIGNCQCMONAWOL-UHFFFAOYSA-N 0.000 description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 2
- ODIRBFFBCSTPTO-UHFFFAOYSA-N 1,3-selenazole Chemical group C1=C[se]C=N1 ODIRBFFBCSTPTO-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FLHJIAFUWHPJRT-UHFFFAOYSA-N 2,3,3-trimethylindole Chemical compound C1=CC=C2C(C)(C)C(C)=NC2=C1 FLHJIAFUWHPJRT-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QWSAXMLCOMNYLR-UHFFFAOYSA-L C[Y]C(C(=O)[O-])[Y]([Y])C(=O)[O-] Chemical compound C[Y]C(C(=O)[O-])[Y]([Y])C(=O)[O-] QWSAXMLCOMNYLR-UHFFFAOYSA-L 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- CFADUJNDPKHQBD-UHFFFAOYSA-N O.C=1C=CC=CC=1N=CC=CC(C)=CNC1=CC=CC=C1 Chemical compound O.C=1C=CC=CC=1N=CC=CC(C)=CNC1=CC=CC=C1 CFADUJNDPKHQBD-UHFFFAOYSA-N 0.000 description 2
- TYOXMPVNNVCHDZ-QRPNPIFTSA-N O.CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C Chemical compound O.CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C TYOXMPVNNVCHDZ-QRPNPIFTSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- KXNQKOAQSGJCQU-UHFFFAOYSA-N benzo[e][1,3]benzothiazole Chemical group C1=CC=C2C(N=CS3)=C3C=CC2=C1 KXNQKOAQSGJCQU-UHFFFAOYSA-N 0.000 description 2
- WMUIZUWOEIQJEH-UHFFFAOYSA-N benzo[e][1,3]benzoxazole Chemical compound C1=CC=C2C(N=CO3)=C3C=CC2=C1 WMUIZUWOEIQJEH-UHFFFAOYSA-N 0.000 description 2
- 238000001574 biopsy Methods 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
- 201000011510 cancer Diseases 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 238000004163 cytometry Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- KSOXXQBOWNEUDA-UHFFFAOYSA-N (4-methyl-2-sulfanylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C(S)=C1 KSOXXQBOWNEUDA-UHFFFAOYSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GTDUGNCNZNUGLP-UHFFFAOYSA-N 1,3-diethyl-2h-imidazo[4,5-b]quinoxaline Chemical compound C1=CC=C2N=C3N(CC)CN(CC)C3=NC2=C1 GTDUGNCNZNUGLP-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- FCTIZUUFUMDWEH-UHFFFAOYSA-N 1h-imidazo[4,5-b]quinoxaline Chemical group C1=CC=C2N=C(NC=N3)C3=NC2=C1 FCTIZUUFUMDWEH-UHFFFAOYSA-N 0.000 description 1
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical compound ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- MHIITNFQDPFSES-UHFFFAOYSA-N 25,26,27,28-tetrazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1(25),2,4,6,8(27),9,11,13,15,17,19,21,23-tridecaene Chemical compound N1C(C=C2C3=CC=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 MHIITNFQDPFSES-UHFFFAOYSA-N 0.000 description 1
- KFKRXESVMDBTNQ-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-8,13-bis(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical compound N1C2=C(C)C(C(C)O)=C1C=C(N1)C(C)=C(C(O)C)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 KFKRXESVMDBTNQ-UHFFFAOYSA-N 0.000 description 1
- MUNOBADFTHUUFG-UHFFFAOYSA-N 3-phenylaniline Chemical group NC1=CC=CC(C=2C=CC=CC=2)=C1 MUNOBADFTHUUFG-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- DRORSPJLYCDESA-UHFFFAOYSA-N 4,4-dimethylcyclohexene Chemical group CC1(C)CCC=CC1 DRORSPJLYCDESA-UHFFFAOYSA-N 0.000 description 1
- SUJVAMIXNUAJEY-UHFFFAOYSA-N 4,4-dimethylhex-1-ene Chemical group CCC(C)(C)CC=C SUJVAMIXNUAJEY-UHFFFAOYSA-N 0.000 description 1
- IFEPGHPDQJOYGG-UHFFFAOYSA-N 4-chloro-1,3-benzothiazole Chemical compound ClC1=CC=CC2=C1N=CS2 IFEPGHPDQJOYGG-UHFFFAOYSA-N 0.000 description 1
- SRGCYOMCADXFJA-UHFFFAOYSA-N 4-methyl-4,5-dihydro-1,3-thiazole Chemical compound CC1CSC=N1 SRGCYOMCADXFJA-UHFFFAOYSA-N 0.000 description 1
- GHAFJOZKMUPGRQ-UHFFFAOYSA-N 4-nitro-1,3-oxazole Chemical compound [O-][N+](=O)C1=COC=N1 GHAFJOZKMUPGRQ-UHFFFAOYSA-N 0.000 description 1
- MLBGDGWUZBTFHT-UHFFFAOYSA-N 4-phenyl-1,3-selenazole Chemical compound [se]1C=NC(C=2C=CC=CC=2)=C1 MLBGDGWUZBTFHT-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- LHYUIVFVDBSPQD-PLSMUUBPSA-N C.C1=CC=C(/N=C/C=C/C=C/NC2=CC=CC=C2)C=C1.CC1=NC2=C(C=C(Br)C=C2)C1(C)C.CC1=NC2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.CC1=[N+](CCCCSO[O-])C2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.Cl.OB(O)C1=CC=CC=C1 Chemical compound C.C1=CC=C(/N=C/C=C/C=C/NC2=CC=CC=C2)C=C1.CC1=NC2=C(C=C(Br)C=C2)C1(C)C.CC1=NC2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.CC1=[N+](CCCCSO[O-])C2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.Cl.OB(O)C1=CC=CC=C1 LHYUIVFVDBSPQD-PLSMUUBPSA-N 0.000 description 1
- MWXASFBPRKSTQA-PLSMUUBPSA-N C1=CC=C(/N=C/C=C/C=C/NC2=CC=CC=C2)C=C1.CC(=O)C(C)C.CC(=O)O.CC1=NC2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.CC1=[N+](CCCCSO[O-])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.Cl.Cl.NC1=CC(C2=CC=CC=C2)=CC=C1.NNC1=CC(C2=CC=CC=C2)=CC=C1 Chemical compound C1=CC=C(/N=C/C=C/C=C/NC2=CC=CC=C2)C=C1.CC(=O)C(C)C.CC(=O)O.CC1=NC2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.CC1=[N+](CCCCSO[O-])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.Cl.Cl.NC1=CC(C2=CC=CC=C2)=CC=C1.NNC1=CC(C2=CC=CC=C2)=CC=C1 MWXASFBPRKSTQA-PLSMUUBPSA-N 0.000 description 1
- ZXWSMLTWLFTHFJ-ZVFBEDIGSA-O C1=CC=C(/N=C/C=C/NC2=CC=CC=C2)C=C1.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1=NC2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CCC(C)NC(=O)CCN1C2=C(C3=C(C=CC=C3)C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](CCC(=O)NC(C)CC(=O)OC(C)(C)C)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)CC[N+]1=C(C)C(C)(C)C2=C1C=CC1=C2C=CC=C1.Cl.ClC1=CC=CC=C1Cl.O=C(O)C(F)(F)F.O=C(O)CCBr.[Cl-] Chemical compound C1=CC=C(/N=C/C=C/NC2=CC=CC=C2)C=C1.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1=NC2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CCC(C)NC(=O)CCN1C2=C(C3=C(C=CC=C3)C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](CCC(=O)NC(C)CC(=O)OC(C)(C)C)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)CC[N+]1=C(C)C(C)(C)C2=C1C=CC1=C2C=CC=C1.Cl.ClC1=CC=CC=C1Cl.O=C(O)C(F)(F)F.O=C(O)CCBr.[Cl-] ZXWSMLTWLFTHFJ-ZVFBEDIGSA-O 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- KUPXLFDOTGQAKE-UHFFFAOYSA-R CC(/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC(/C=C/C=C1/N(CCC(=O)NC(CCC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CCC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC(/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C)=C\C=C\C1=[N+](CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C.CC1(C)C2=C(C=CC=C2)[N+](CCCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F Chemical compound CC(/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC(/C=C/C=C1/N(CCC(=O)NC(CCC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CCC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC(/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C)=C\C=C\C1=[N+](CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C.CC1(C)C2=C(C=CC=C2)[N+](CCCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F KUPXLFDOTGQAKE-UHFFFAOYSA-R 0.000 description 1
- NBSQKDOMEXDBQT-UHFFFAOYSA-A CC(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)O[Na])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC(/C=C/C=C1/N(CCCCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCCCC(=O)O[Na])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(Cl)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CCC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(N(C2=CC=CC=C2)C2=CC=CC=C2)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(SC2=C(C(=O)O[K])C=CC=C2)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CCC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)C1=CC=CC=C1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)CC1=CC=CC=C1.CCOC(=O)N1CCN(C2=C(/C=C/C3=[N+](CC(=O)O[K])C4=C(C=C(SOO[O-])C=C4)C3(C)C)CC/C2=C\C=C2\N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CC1 Chemical compound CC(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)O[Na])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC(/C=C/C=C1/N(CCCCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCCCC(=O)O[Na])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(Cl)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CCC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(N(C2=CC=CC=C2)C2=CC=CC=C2)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CC(=O)O[K])=C1/C=C/C1=C(SC2=C(C(=O)O[K])C=CC=C2)/C(=C/C=C2/N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CCC1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)C1=CC=CC=C1.CC1(C)C2=C(C=CC(SOO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C(/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)CC1=CC=CC=C1.CCOC(=O)N1CCN(C2=C(/C=C/C3=[N+](CC(=O)O[K])C4=C(C=C(SOO[O-])C=C4)C3(C)C)CC/C2=C\C=C2\N(CC(=O)O[K])C3=C(C=C(S(=O)(=O)O[K])C=C3)C2(C)C)CC1 NBSQKDOMEXDBQT-UHFFFAOYSA-A 0.000 description 1
- YHNQKEIXVQYOSU-UHFFFAOYSA-I CC(/C=C/C=C1/N(CCCCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC(C(=O)O)=C2)[N+](CCCCC(=O)NC(COC=O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=C(C(=O)O)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C=C(S(=O)(=O)[O-])C=C2)C1(C)C.O=C([O-])C(F)(F)F Chemical compound CC(/C=C/C=C1/N(CCCCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC(C(=O)O)=C2)[N+](CCCCC(=O)NC(COC=O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=C(C(=O)O)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C=C(S(=O)(=O)[O-])C=C2)C1(C)C.O=C([O-])C(F)(F)F YHNQKEIXVQYOSU-UHFFFAOYSA-I 0.000 description 1
- WETJLQYXIXBQJV-UHFFFAOYSA-H CC(/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)O[K])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC1(C)C2=C(C=C(C3=CC=CC=C3)C=C2)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.CC1(C)C2=C(C=CC(C3=CC=CC=C3)=C2)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC(C3=CC=CS3)=C2)[N+](CCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCS(=O)(=O)O[K])C2=C(C=C(C3=CC=CS3)C=C2)C1(C)C.CSC1=CC=C(C2=CC3=C(C=C2)[N+](CCCCSOO[O-])=C(/C=C/C=C/C=C/C=C2/N(CCCCS(=O)(=O)O[K])C4=C(C=C(C5=CC=C(SC)C=C5)C=C4)C2(C)C)C3(C)C)C=C1 Chemical compound CC(/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C)=C\C=C\C1=[N+](CCC(=O)O[K])C2=C(C=C(SOO[O-])C=C2)C1(C)C.CC1(C)C2=C(C=C(C3=CC=CC=C3)C=C2)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=CC(C3=CC=CC=C3)=C2)C1(C)C.CC1(C)C2=C(C=CC(C3=CC=CC=C3)=C2)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[K])C2=C(C=C(C3=CC=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC(C3=CC=CS3)=C2)[N+](CCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCS(=O)(=O)O[K])C2=C(C=C(C3=CC=CS3)C=C2)C1(C)C.CSC1=CC=C(C2=CC3=C(C=C2)[N+](CCCCSOO[O-])=C(/C=C/C=C/C=C/C=C2/N(CCCCS(=O)(=O)O[K])C4=C(C=C(C5=CC=C(SC)C=C5)C=C4)C2(C)C)C3(C)C)C=C1 WETJLQYXIXBQJV-UHFFFAOYSA-H 0.000 description 1
- XYHZXXNRCDWEGO-UHFFFAOYSA-K CC(/C=C/C=C1/N(CCS(=O)(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCSOO[O-])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C Chemical compound CC(/C=C/C=C1/N(CCS(=O)(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C)=C\C=C\C1=[N+](CCSOO[O-])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C XYHZXXNRCDWEGO-UHFFFAOYSA-K 0.000 description 1
- KYXZJBHFMTUBMT-WOINNPJESA-N CC(/C=C/NC1=CC=CC=C1)=C\C=N\C1=CC=CC=C1.CC1=NC2=C(C=C(SOOO)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)CC[N+]1=C(C)C(C)(C)C2=C1C=CC(SOO[O-])=C2.CCN(CC)CC.Cl.O=C(O)CCBr Chemical compound CC(/C=C/NC1=CC=CC=C1)=C\C=N\C1=CC=CC=C1.CC1=NC2=C(C=C(SOOO)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)CC[N+]1=C(C)C(C)(C)C2=C1C=CC(SOO[O-])=C2.CCN(CC)CC.Cl.O=C(O)CCBr KYXZJBHFMTUBMT-WOINNPJESA-N 0.000 description 1
- SDEPUDWIQKHWJN-UHFFFAOYSA-N CC(=O)O.CC(N)=O.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1.CCC(=O)O.CCC(N)=O.CCS(=O)(=O)O.CCS(N)(=O)=O.CS(=O)(=O)O.CS(N)(=O)=O Chemical compound CC(=O)O.CC(N)=O.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1.CC1=CC=CC=C1.CCC(=O)O.CCC(N)=O.CCS(=O)(=O)O.CCS(N)(=O)=O.CS(=O)(=O)O.CS(N)(=O)=O SDEPUDWIQKHWJN-UHFFFAOYSA-N 0.000 description 1
- AYEMQNZHYOQMRW-UHFFFAOYSA-N CC(N)=O.CC1=CC=CC=C1.CCC(N)=O Chemical compound CC(N)=O.CC1=CC=CC=C1.CCC(N)=O AYEMQNZHYOQMRW-UHFFFAOYSA-N 0.000 description 1
- FSPSZQTWWBRJQA-UHFFFAOYSA-K CC1(C)C2=C(C=CC(SO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC(SO[O-])=C2)[N+](CCC(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O[Na])C2=C(C=C(S(=O)(=O)O[Na])C=C2)C1(C)C FSPSZQTWWBRJQA-UHFFFAOYSA-K 0.000 description 1
- FATZCFRPYLDATQ-UHFFFAOYSA-L CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)[O-])C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)[O-])C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F Chemical compound CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O[Na])C(=O)O[Na])C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)[O-])C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)[O-])C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=C(C=CC=C3)C=C2)C1(C)C.O=C([O-])C(F)(F)F.O=C([O-])C(F)(F)F FATZCFRPYLDATQ-UHFFFAOYSA-L 0.000 description 1
- YQRKWNAPKJQWSX-UHFFFAOYSA-N CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)[O-])C2=C(C=CC=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC(Br)=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCC(=O)NC(CC(=O)O)C(=O)O)=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)[O-])C2=C(C=CC=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC(Br)=C2)C1(C)C.CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCC(=O)NC(CC(=O)O)C(=O)O)C2=C(C=CC=C2)C1(C)C YQRKWNAPKJQWSX-UHFFFAOYSA-N 0.000 description 1
- ARDWBACPRMJNJN-UHFFFAOYSA-N CC1=NC2=C(C3=C(C=C2)C=C(SOOO)C=C3)C1(C)C.CC1=NC2=C(C3=C(C=CC=C3)C=C2)C1(C)C Chemical compound CC1=NC2=C(C3=C(C=C2)C=C(SOOO)C=C3)C1(C)C.CC1=NC2=C(C3=C(C=CC=C3)C=C2)C1(C)C ARDWBACPRMJNJN-UHFFFAOYSA-N 0.000 description 1
- BKJPEXJWIYPHHK-AVHXYYTHSA-N CC1=NC2=C(C=C(SOOO)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)C[N+]1=C(C)C(C)(C)C2=C1C=CC(SOO[O-])=C2.CCN(CC)CC.CCN(CC)CC.Cl.ClC1=C(/C=N/C2=CC=CC=C2)CCC/C1=C\NC1=CC=CC=C1.O=C(O)C1=C(S)C=CC=C1.O=C(O)CCBr Chemical compound CC1=NC2=C(C=C(SOOO)C=C2)C1(C)C.CCN(CC)(CC)OC(=O)C[N+]1=C(C)C(C)(C)C2=C1C=CC(SOO[O-])=C2.CCN(CC)CC.CCN(CC)CC.Cl.ClC1=C(/C=N/C2=CC=CC=C2)CCC/C1=C\NC1=CC=CC=C1.O=C(O)C1=C(S)C=CC=C1.O=C(O)CCBr BKJPEXJWIYPHHK-AVHXYYTHSA-N 0.000 description 1
- JRLPEMVDPFPYPJ-UHFFFAOYSA-N CCC1=CC=C(C)C=C1 Chemical compound CCC1=CC=C(C)C=C1 JRLPEMVDPFPYPJ-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- LIQQDSFFUGIJFR-UHFFFAOYSA-N Cl.C=1C=CC=CC=1N=CC=C(C)C=CNC1=CC=CC=C1 Chemical compound Cl.C=1C=CC=CC=1N=CC=C(C)C=CNC1=CC=CC=C1 LIQQDSFFUGIJFR-UHFFFAOYSA-N 0.000 description 1
- DUHVQBLYNNZATN-UHFFFAOYSA-N Cl.C=1C=CC=CC=1N=CC=CC(C)=CNC1=CC=CC=C1 Chemical compound Cl.C=1C=CC=CC=1N=CC=CC(C)=CNC1=CC=CC=C1 DUHVQBLYNNZATN-UHFFFAOYSA-N 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IJEXZFWSXVMPTM-UHFFFAOYSA-N N-(5-phenyliminopenta-1,3-dienyl)aniline hydrate Chemical compound O.C=1C=CC=CC=1NC=CC=CC=NC1=CC=CC=C1 IJEXZFWSXVMPTM-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- ZQJGXYTYMHKWGG-UHFFFAOYSA-M [H]C(O)(CO)C([H])(O)C([H])(O)C(O)NC(=O)C1=CC2=C(C=C1)[N+](CCCCSO[O-])=C(/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[Na])C3=C(C=C(C(=O)NCC([H])(O)C([H])(O)C([H])(O)C([H])(O)CO)C=C3)C1(C)C)C2(C)C Chemical compound [H]C(O)(CO)C([H])(O)C([H])(O)C(O)NC(=O)C1=CC2=C(C=C1)[N+](CCCCSO[O-])=C(/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O[Na])C3=C(C=C(C(=O)NCC([H])(O)C([H])(O)C([H])(O)C([H])(O)CO)C=C3)C1(C)C)C2(C)C ZQJGXYTYMHKWGG-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AMTXUWGBSGZXCJ-UHFFFAOYSA-N benzo[e][1,3]benzoselenazole Chemical compound C1=CC=C2C(N=C[se]3)=C3C=CC2=C1 AMTXUWGBSGZXCJ-UHFFFAOYSA-N 0.000 description 1
- IEICFDLIJMHYQB-UHFFFAOYSA-N benzo[g][1,3]benzoselenazole Chemical compound C1=CC=CC2=C([se]C=N3)C3=CC=C21 IEICFDLIJMHYQB-UHFFFAOYSA-N 0.000 description 1
- IIUUNAJWKSTFPF-UHFFFAOYSA-N benzo[g][1,3]benzothiazole Chemical compound C1=CC=CC2=C(SC=N3)C3=CC=C21 IIUUNAJWKSTFPF-UHFFFAOYSA-N 0.000 description 1
- BVVBQOJNXLFIIG-UHFFFAOYSA-N benzo[g][1,3]benzoxazole Chemical compound C1=CC=CC2=C(OC=N3)C3=CC=C21 BVVBQOJNXLFIIG-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N but-2-ene Chemical group CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- MMJGQHYROJTOHX-JTQLQIEISA-N dibutyl (2s)-2-aminobutanedioate Chemical compound CCCCOC(=O)C[C@H](N)C(=O)OCCCC MMJGQHYROJTOHX-JTQLQIEISA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- ZZZGFHPVTUKOSU-FVGYRXGTSA-N ditert-butyl (2s)-2-aminopentanedioate;hydrate Chemical compound O.CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C ZZZGFHPVTUKOSU-FVGYRXGTSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- ZFKJVJIDPQDDFY-UHFFFAOYSA-N fluorescamine Chemical compound C12=CC=CC=C2C(=O)OC1(C1=O)OC=C1C1=CC=CC=C1 ZFKJVJIDPQDDFY-UHFFFAOYSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004220 fundus oculi Anatomy 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 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 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 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
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- XUZLXCQFXTZASF-UHFFFAOYSA-N nitro(phenyl)methanol Chemical compound [O-][N+](=O)C(O)C1=CC=CC=C1 XUZLXCQFXTZASF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
Definitions
- the present invention relates to a near infrared fluorescent contrast agent, and a method of fluorescence imaging using said near infrared fluorescent contract agent.
- One of reported image diagnoses includes fluorescence imaging (Lipspn R. L. et al., J. Natl. Cancer Inst., 26, 1-11 (1961)).
- This method employs a substance as a contrast agent that emits fluorescence upon exposure to an excitation light having a specific wavelength.
- the method comprises the step of exposing a body with an excitation light from outside the body and then detecting fluorescence emitted from the fluorescent contrast agent in vivo.
- fluorescent contrast agent examples include, for example, a porphyrin compound that accumulates in tumor and is used for photodynamic therapy (PDT), e.g., haematoporphyrin.
- PDT photodynamic therapy
- Other examples include photophyrin and benzoporphyrin (see, Lipspn R. L. et al., supra, Meng T. S. et al., SPIE, 1641, 90-98 (1992), WO84/04665 an the like).
- these compounds have phototoxicity since they are originally used for PDT (PDT requires such property), and accordingly, these compounds are not desirable as diagnostic agents.
- Retinal circulatory microangiography using a known fluorescent dye such as fluorescein, fluorescamine, and riboflabin, has been known (U.S. Pat. No. 4,945,239).
- fluorescent dyes emit fluorescence in a region of a visible light of 400-600 nm which only achieves low transmission through living tissue, and consequently, detection of a lesion in a deeper part of a body is almost impossible.
- Cyanine compounds including indocyanine green (hereinafter abbreviated as “ICG”), which are used to determine liver function and cardiac output, have been also reported to be useful as fluorescent contrast agents (Haglund M. M. et al., Neurosurgery, 35, 930 (1994), Li, X. et al., SPIE, 2389, 789-797 (1995)). Cyanine compounds have absorbance in a near infrared light region (700 to 1300 nm).
- Near infrared light has a high transmission property through living tissues and can pass through the skull of about 10 cm, and from these reasons, said light has been focused recently in the filed of clinical medicine.
- the optical CT technique (a CT technique using optical transmission of a medium) has become focused as a new technology in the clinical flied, because near infrared light can pass through a living body and, oxygen concentration and circulation in vivo can be detected by using a light within this region.
- the cyanine compound emits fluorescence in the near infrared region, a light of which region has excellent permeability in living tissues as explained above, and accordingly a use as a fluorescent contrast agent has been proposed.
- Various cyanine compounds have been developed in recent years, and approaches for use as fluorescent contrast agents have been made (WO96/17629, WP97/13490 and the like).
- an agent having a satisfactory distinguishing ability of a lesion from normal tissues i.e., an agent having a satisfactory selectively to a target site to be imaged, has not yet been available.
- the inventors of the present invention conducted various studies to achieve the foregoing objects. As a result, by introducing carboxylic acid or an aryl group to cyanine dyes, they succeeded in providing a fluorescent contrast agent having high tumor selectivity. They also succeeded in establishing a method for fluorescence imaging by using said contrast agent.
- the present invention was achieved on the basis of the above findings.
- the present invention thus provides a near infrared fluorescent contrast agent comprising a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 7 , and R 8 independently represent a substituted or unsubstituted C 1 -C 10 alkyl group or a substituted or unsubstituted aryl group, and R 1 and R 2 and/or R 7 and R 8 may bind to each other to form a ring;
- R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 independently represent a hydrogen atom, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a halogen atom, cyano group, carboxyl group, or sulfo group, and R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 may bind to each other to form a ring;
- each of m 1 , m 2 , and m 3 is simultaneously 1, and X 1 is a group represented by the following formula (i):
- Y 1 and Y 2 independently represent a substituted or unsubstituted divalent linking group.
- X 1 and X 2 independently represent a group represented by the following formula (i):
- Y 1 and Y 2 independently represent a substituted or unsubstituted a divalent bond.
- At least one of R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group
- at least one of R 4 , R 5 , R 10 , and R 11 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group
- each of X 1 and X 2 is independently a C 1 -C 6 carboxylalkyl group or a sulfoalkyl group.
- X 1 and X 2 independently represent a group represented by the following formula:
- Y 3 represents a C 1 -C 10 hydrocarbon group and at least one of the methine groups represented by L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is a substituted methine group and each of R 4 and R 10 is a sulfo group.
- the number of sulfo group in a molecule is two or less.
- Y 1 represents —(CH 2 ) p CONH—wherein p represents an integer of 1 to 4 and Y 2 represents —(CH 2 )— or (CH 2 ) 2 —.
- the aforementioned near infrared fluorescent contrast agent may preferably be used for tumor imaging or angiography.
- a method of fluorescence imaging which comprises the steps of introducing the aforementioned near infrared fluorescent contrast agent into a living body, exposing said body to an excitation light, and detecting near infrared fluorescence from the contrast agent.
- FIG. 1 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 2 of the present invention.
- FIG. 2 is a photograph showing the results of fluorescence imaging at given times after the administration of ICG as a reference.
- FIG. 3 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound A as a reference.
- FIG. 4 is a schematic view of experimental set up for fluorescence imaging in Test Example 2.
- SHG represents second harmonic generation
- THG represents third harmonic generation
- OPO represents optical parametric oscillator.
- FIG. 5 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 5 of the present invention.
- FIG. 6 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 7 of the present invention.
- FIG. 7 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 10 of the present invention.
- FIG. 8 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound B as a reference.
- the C 1 -C 10 alkyl group represented by R 1 , R 2 , R 7 , and R 8 may be linear, branched, cyclic, or a combination thereof (an alkyl group and an alkyl moiety of a functional group containing the alkyl moiety have the same meaning in the specification unless otherwise specifically mentioned).
- an alkyl group and an alkyl moiety of a functional group containing the alkyl moiety have the same meaning in the specification unless otherwise specifically mentioned.
- the unsubstituted alkyl group for example, methyl group, ethyl group, propyl group, butyl group, and hexyl group can be used.
- the number, kind, or position of substituents on the substituted alkyl group are not particularly limited.
- substituted alkyl for example, sulfoalkyl group, carboxylalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, halogenated alkyl group, cyanoalkyl group, aryl-substituted alkyl group, heteroaryl-substituted alkyl group and the like can be used.
- the aryl group represented by R 1 , R 2 , R 7 , and R 8 may be either a monocyclic ring or a condensed ring, for example, a C 6 -C 14 aryl group, preferably C 6 -C 10 aryl group can be used (an aryl group and an aryl moiety of a functional group containing the aryl moiety have the same meaning unless otherwise specifically mentioned).
- a aryl group preferably phenyl group or naphthyl group, more preferably phenyl group may used.
- substituted aryl group sulfophenyl group, hydroxyphenyl group, aminophenyl group can be used.
- R 1 and R 2 , R 7 and R 8 may bind to each other to form a ring.
- the ring formed include, for example, cyclopentyl ring, cyclohexyl ring and the like.
- R 1 , R 2 , R 7 , and R 8 are preferably methyl group or ethyl group, more preferably methyl group.
- R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 independently represent a hydrogen atom, a substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a halogen atom, cyano group, carboxyl group, or sulfo group, and two adjacent groups selected from the group consisting of R 3 , R 4 , R 5 , and R 6 or those selected from the group consisting of R 9 , R 10 , R 11 , and R 12 may independently bind to each other to form a ring.
- the ring formed may be saturated or unsaturated, and may be a hydrocarbon ring or a heterocyclic ring.
- R 3 and R 4 , R 4 and R 5 , R 5 and R 6 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 can bind to each other to form a benzene ring or an aromatic heterocyclic ring such as pyridine ring.
- Preferred examples include a benzene ring formed by binding of R 3 and R 4 , or R 9 and R 10 .
- aryl group represented by R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 for example, phenyl group or naphthyl, group can be used, as the heteroaryl group, for example, thienyl group, benzothienyl group, furyl group, benzofuryl group, pyrrolyl group, imidazolyl group, or quinolyl group can be used.
- One to four optional substituents may be present on the aryl group and the heteroaryl group. The position of the substituents is not limited, and when two or more substituents are present, they may be same or different.
- substituents for example, hydroxyl group, a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C 1 -C 6 alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group; C 1 -C 6 halogenated alkyl group such as trifluoromethyl group; a C 1 -C 6 alkoxyl group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group; a C 1 -C 6 alkylenedioxy group such as methylenedioxy group, ethylenedioxy group; carboxyl group; a C 1 -C 6 alkoxycarbonyl group; an unsubstituted amino group
- X 1 and X 2 independently represent a substituted or unsubstituted C 1 -C 15 alkyl group or a substituted or unsubstituted aryl group, and X 1 and X 2 have one to four carboxyl groups in total of X 1 and X 2 .
- unsubstituted alkyl represented by X 1 and X 2 for example, methyl group, ethyl group, propyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 2-methylpropyl group, or 1,1-dimethylpropyl group can be used.
- the alkyl group may be linear, branched, cyclic, or a combination thereof, and a linear or branched alkyl group is preferred.
- a sulfoalkyl group such as 2-sulfoethyl group, 3-sulfopropyl group, 3-methyl-3-sulfopropyl group, 4-sulfobutyl group and the like
- a carboxyalkyl group such as 1-carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the like
- a hydroxyalkyl group such as 1-carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the like
- a hydroxyalkyl group such as 1-carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the like
- a hydroxyalkyl group such as 1-carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the
- alkyl moiety of these groups is the same as those defined in the above-mentioned unsubstituted alkyl group.
- substituted or unsubstituted aryl group represented by R 1 , R 2 , R 7 , and R 8 phenyl group, sulfophenyl group, hydroxyphenyl group, or aminophenyl group can be used.
- a C 1 -C 5 carboxyalkyl group or a sulfoalkyl group can be used as the X 1 and X 2 .
- a substituted or unsubstituted C 1 -C 6 alkylene group such as methylene group, ethylene group, n-butylene group, methylpropylene group, or phenylene group can be used.
- a linking group represented by the following formula can be used:
- hydrocarbon groups may have substituents and may contain one or more hetero atoms.
- they may contain an ether bond, a thioether bond, a disulfide bond, an amide bond, an ester bond, a sulfonamide bond, or a sulfoester bond.
- a bond represented by the following formula can also be used:
- Y 1 include a linking group represented by the following formula:
- Y 1 is —(CH 2 ) p —CO—NH— (wherein p represents an integer of 1 to 4).
- Preferred examples of Y 2 include methylene group or ethylene group.
- L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 independently represent a substituted or unsubstituted methine group, wherein m 1 , m 2 , and m 3 independently represent 0 or 1. It is preferred that each of m 1 , m 2 , and m 3 is simultaneously 1.
- substituent on the methine group include a substituted or unsubstituted alkyl group, a halogen atom, a substituted or unsubstituted aryl group, or a lower alkoxy group and the like.
- An specific examples of the substituted aryl group includes 4-chlorophenyl group and the like.
- the lower alkoxy group may preferably be a C 1 -C 6 alkoxy group which may be linear or branched. Specific examples include methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, pentyloxy group and the like, and methoxy group or ethoxy group is preferred. As the substituent of the methine group, methyl group or phenyl group can preferably be used.
- the substituents on the methine groups may bind to each other to form a ring.
- the substituents on the methine groups may bind to form a ring containing three successive methine group selected from the group consisting of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 .
- substituents on the methine groups bind to each other to form a ring containing three successive methine group selected from the group of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 include, for example, a compound wherein 4,4-dimethylcyclohexene ring is formed to contain L 3 , L 4 , and L 5 .
- a particularly preferred example of a partial structure in which a conjugated methine chain formed by methine groups selected from the group of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 contains a ring includes a group represented by the following general formula (a):
- Z represents a nonmetallic atom group necessary for forming a 5- or 6-membered ring
- A represents a hydrogen atom or a monovalent group
- Examples of the nonmetallic atom group necessary for forming a 5- to 10-membered ring represented by Z include, for example, a carbon atom, a nitrogen atom, an oxygen atom, a hydrogen atom, a sulfur atom, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) and the like.
- Examples of the 5- or 6-membered ring in the partial structure represented by the general formula (a) include, for example, cyclopentene ring, cyclohexene ring, and 4,4-dimethylhexene ring, and cyclopentene ring or cyclohexene ring is preferred.
- Examples of the monovalent group represented by A include, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkylcarbonyloxy group (such as acetoxy group), a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, cyano group, nitro group, a halogen atom and the like.
- aralkyl group represented by A examples include benzyl group, 2-phenylethyl group, 3-phenylpropyl and the like.
- substituent of the aralkyl group include, for example, sulfo group, carboxyl group, hydroxyl group, a substituted or unsubstituted alkyl, group, an alkoxy group, a halogen atom and the like.
- substituted amino group represented by A examples include, for example, an alkylamino group (such as methylamino group, ethylamino group and the like), a dialkylamino group (such as dimethyl amino group, diethylamino group and the like), phenylamino group, diphenylamino group, methylphenylamino group, a cyclic amino group (such as morpholino group, imidazolidino group, ethoxycarbonylpiperadino group and the like).
- an alkylamino group such as methylamino group, ethylamino group and the like
- a dialkylamino group such as dimethyl amino group, diethylamino group and the like
- phenylamino group diphenylamino group
- methylphenylamino group methylphenylamino group
- a cyclic amino group such as morpholino group, imidazolidino group, ethoxycarbon
- arylthio group represented by A examples include phenylthio group, naphthylthio group and the like, and examples of a substituent of the arylthio group include sulfo group, carboxyl group and the like.
- Examples of the monovalent group represented by A include phenylamino group, diphenylamino group, ethoxycarbonyl piperazino group, arylthio group and the like.
- Y represents a nonmetallic atom necessary for forming a 5- to 10-membered heterocyclic ring, preferably, a 5- or 6-membered heterocyclic ring (the heterocyclic ring may be a condensed ring).
- the 5- to 10-membered heterocyclic ring formed by Y include the following rings: thiazole ring (such as thiazole, 4-methylthiazole and the like), benzothiazole ring (such as benzothiazole, 4-chlorobenzothiazole and the like), naphthothiazole ring (such as naphtho[2,1-d]-thiazole, naphtho[1,2-d]thiazole and the like), thiazoline ring (such as thiazoline, 4-methylthiaazoline and the like), oxazole ring (such as oxazole, 4-nitrooxazole and the like), benzoxazole (such as benzoxazole, 4-chrolobenzoxazole and the like
- M represents hydrogen atom, a metal, quaternary ammonium salt, or other pharmaceutically acceptable salts.
- the “pharmaceutically acceptable salts” may be any salt which can form nontoxic salts with the compound represented by the general formula [I]. Examples include, for example, alkaline metal salt such as a sodium salt, a potassium salt and the like; alkaline-earth metal salt such as a magnesium salt, a calcium salt and the like; organic ammonium salt such as a ammonium salt, a triethyl ammonium salt, tributyl ammonium salt, pyridinium salt and the like; salt of amino acid such as lysine salt, arginine salt and the like. Particularly preferred is a sodium salt with a reduced toxicity to a living body.
- the compound of the present invention may have one or more asymmetric carbon atoms depending on the kind of substituents. Sulfur atoms may act as asymmetric center. Any optical isomers in an optically pure form based on one or more asymmetric carbon atoms, any mixture of the above optical isomers, racemates, diastereomers based on two or more asymmetric carbon atoms, any mixture of the above diastereomers and the like fall within the scope of the present invention.
- the cyanine dye represented by the formula [I] or [II] can be synthesized according to known preparation methods of cyanine dye compounds, for example, those disclosed in the Cyanine Dyes and Related Compounds, F. M. Hamer, John Wiley and Sons, New York, 1964, Cytometry, 11, 416-430 (1990), Cytometry, 12, 723-730 (1990), Bioconjugate Chem, 4, 105-111 (1993), Anal. Biochem., 217, 197-204 (1994), Tetrahedron, 45, 4845-4866 (1989), EP-A-0591820A1, EP-A-0580145A1 and the like.
- they can be semisynthesized from a commercially available cyanine dye compound by known methods. More specifically, they can be synthesized by reacting a diaryl compound with a heterocyclic quaternary salt.
- the methods for preparing the cyanine dye compounds represented by the above formula [I] or [II] are not particularly limited, and the compounds can be synthesized by various synthetic routes. Specific preparations of typical compounds of the present invention are disclosed in the Examples of the specification. Accordingly, one of ordinary skill in the art can prepare the cyanine dye compounds that falls within the scope of the above general formulas by referring to the methods described in the Examples, and if necessary, by adding appropriate alteration or modification to the methods and by appropriately choosing starting materials and reagents. For the preparation, a reaction selected from various reactions such as condensation, addition, oxidation, reduction and the like may be employed alone or in combination. These reactions are explained in detail in the literature.
- a desirable step can be sometimes conducted efficiently by utilizing various methods which are conventionally used in the filed of organic synthetic chemistry, for example, means for protection or deprotection of functional groups, or treatments such as oxidation, reduction, hydrolysis and the like.
- Synthetic intermediate compounds and the target compounds in the above steps can be isolated and purified by conventional purification methods used in organic synthetic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography and the like. The synthetic intermediate products can be used in the next reaction without isolation.
- the compound represented by the general formula [I] in or [II] or a salt thereof may be used alone or in combination. More specifically, the active ingredient may be contained in the contrast agent in a form of a suspension or a solution in a solvent such as injectable distilled water, physiological saline, Ringer's solution and the like.
- Additives such as pharmaceutically acceptable carrier, excipients and the like may also be formulated, if desired. Examples of these additives include substances such as pharmaceutically acceptable electrolytic solutions, buffering solutions, detergents, and substances for adjusting osmotic pressure, substances for improving stability or solubility such as cyclodextrin, liposome and the like. Any additives ordinarily available in the art may be used.
- the near infrared fluorescent contrast agent of the present invention is preferably synthesized through sterilization processes when used as a medicament for clinical application.
- the contract agent can be administered to a living body by injection, spraying, or topical application such as intravascular application (venous, arterial), oral application, intraperitoneal application, percutaneous application, subcutaneous application, intracystical application, or intrabronchial application.
- the contrast agent may be administered into blood vessels in the form of an aqueous solution, an emulsion or a suspension.
- the dose of the near infrared fluorescent contrast agent of the present invention is not particularly limited insofar as the dose enables detection of a site to be diagnosed.
- the dose may appropriately be increased or decreased depending on the type of the compound to be used that emits near infrared fluorescence, the age, body weight and a target organ of a subjects to be administered and the like.
- the dose as the weight of the compound may be 0.1 to 100 mg/kg body weight, preferably 0.5 to 20 mg/kg body weight.
- the contrast agent of the present invention may also be appropriately used for various animals other than human.
- a formulation for administration, the route of administration, a dose and the like may be appropriately chosen depending on the body weight and conditions of the target animals.
- the compounds of the present invention represented by the above formula [I] and [II] have property to highly accumulated in tumor tissues. Utilizing said property, the present invention also provides the fluorescent contrast agent which enables specific imaging of a tumor tissue. In addition, the class of the compounds of the present invention have long-term retention in blood vessels, and therefore, the fluorescent contrast agent of the present invention is also useful for angiography.
- the method for fluorescence imaging of the present invention is characterized by the use of the near infrared fluorescent contrast agent of the present invention.
- the method for imaging can be carried out by one of ordinary skill in the art according to known methods, and each of parameters such as excitation wavelength and fluorescence wavelength to be detected may appropriately be determined to achieve optimal imaging and evaluation, depending on the kind of near infrared fluorescence contrast agent to be administered and a subject to be administered.
- the period of time from administration of the near infrared fluorescent contrast agent of the present invention to the start of fluorescence imaging according to the present invention may vary depending on the kind of the near infrared fluorescent contrast agent to be used and a subject to be administered.
- a lapse time may be about 10 minutes to 24 hours after administration.
- fluorescence from every site may be still too intense and the target site is not distinguishable from other sites, and when the lapse time is too long, the contrast agent may be excreted from the body.
- the compound of the formula [I] or formula [II] is detected immediately after administration or in about 30 minutes after the administration.
- the fluorescence imaging can be conducted by the following steps.
- a near infrared fluorescent contrast agent of the present invention is administered to a subject to be diagnosed, and then the subject is exposed to an excitation light using an apparatus generating excitation light. Then, fluorescence from the near infrared fluorescent contrast agent, which is generated by the excitation light, is detected by using a fluorescence detector.
- the wavelength for excitation varies depending on the type of the near infrared fluorescent contrast agent to be used, and is not limited as long as the compounds efficiently emits fluorescence in the near infrared region.
- a near infrared light having superior bio-permeability may be used.
- the wavelength of the near infrared fluorescence to be detected also varies depending on the contrast agent to be used.
- an excitation light having a wavelength of 600 to 1000 nm, preferably 700 to 850 nm, may be used and near infrared fluorescence having a wavelength of 700 to 1000 nm, preferably, 750 to 900 nm, may be detected.
- a conventional excitation light source such as various lasers (e.g., ion lased, dye laser and semiconductor laser), halogen light source, xenon light source and the like may be used.
- Various optical filters may be used to obtain optimal excitation wavelength, if desired.
- various optical filters may be used for selection of the fluorescence generated from the near infrared fluorescent contrast agent.
- the detected fluorescence is data-processed as fluorescence information to construct fluorescence images to be recorded.
- Examples of the method for preparation of fluorescence images include, for example, a method comprising the step of irradiating the target tissue in a wide range, detecting fluorescence with a CCD camera, and then image-processing the fluorescence information obtained; a method using an optical CT device; a method using an endoscope; or a method using fundus oculi camera and the like.
- systemic diseases, tumors, blood vessels and the like can be visualized without damaging a living body.
- the starting material 1 (20.9 g, 0.1 mol), 2-bromopropinic acid (23.0 g, 0.15 mol), and o-dichlorobenzene (20 ml) were heated and stirred at 140° C. for 2 hours. After the reaction was completed, the reaction mixture was added with acetone (200 ml) and cooled to room temperature, and then the resultant crystal was filtrated to obtain Intermediate 1 (20.3 g, yield: 56%)
- Compound 1 was purified by column chromatography using Sephadex (LH-20, Pharmacia) (eluent: methanol) to obtain Compound 2.
- Compound 6 was synthesized from Intermediate 1 and 1,7-diaza-5-methyl-1,7-diphenyl-1,3,5-heptatriene monohydrate in a similar manner to that for Compound 1 except that L-glutamic acid-di-t-butylester monohydrate was used instead of L-aspartic acid-di-t-butylester monohydrate.
- Compound 8 was synthesized from 2,3,3-trimethylindolenine in a similar manner to that for Compound 1 except that 1,7-diaza-5-methyl-1,7-diphenyl-1,3,5-heptatriene monohydrochloride was used instead of 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrate.
- Compound 9 was synthesized from 6-phenyl-2,3,3-trimethylindolenine (synthesized by a method described in the specification of the U.S. Pat. No. 6,004,536) in a similar manner to that for Compound 1.
- Compound 10 was synthesized from 6-bromo-2,3,3-trimethyl-indolenine in a similar manner to that for Compound 1.
- Compound 11 was synthesized from 5-phenyl-2,3,3-trimethyl-indolenine in a similar method to that for Compound 1.
- An intermediate compound (375 mg), which was obtained by reacting 5-sulfo-2,3,3-trimethylindolenine (prepared according to the method described in the Japanese Patent Unexamined Publication (KOKAI) No. (Hei)2-233658) and 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrochloride in methanol in the presence of triethylamine and acetic anhydride, was dissolved in 5 ml of methanol, and then applied to an column filled with cationic ion exchange resin IRC-50 (Organo, eluent: methanol). The solvent was evaporated to give the proton form of the carboxylic acid.
- the resulting product was dissolved in 3 ml of dimethylformamide, and the solution was added with 338 mg (1.2 mmol) of dibutyl aspartate hydrochloride, 24 mg (0.2 mmol) of dimethylaminopyridine, and 121 mg (1.2 mmol) of triethylamine, and then the mixture was cooled on ice bath.
- the mixture was added with 230 mg (2 mmol) of hydroxysuccinimide (HOSI) and 288 mg (1.4 mmol) of N,N-dicyclohexyl-carbodiimide (DCC), and the resulting mixture was stirred overnight.
- HOSI hydroxysuccinimide
- DCC N,N-dicyclohexyl-carbodiimide
- the reaction mixture was added with 200 ml of a mixed solvent of ethyl acetate/hexane (1:1) and crystals precipitated were collected by filtration.
- the starting material (41.8 g, 0.2 mol) was dissolved in conc. sulfuric acid (156 ml, 2.9 mol) and reacted at 140° C. for 1 hour, and then the mixture was cooled to 80° C. After the resulting solution was added to ice water (300 ml), a solution obtained by dissolving sodium hydroxide (96.6 g, 2.4 mol) in water (100 ml) was carefully added to the mixture. The crystals precipitated were collected by filtration and washed with water (120 ml). The resulting crude crystal was added with water (300 ml) and methanol (100 ml), and the mixture was refluxed under stirring for 30 minutes, and then cooled to room temperature. The resulting crystals were collected by filtration and washed with water (100 ml) and methanol (120 ml) to obtain Intermediate 5 (37.9 g, yield: 66%).
- Compound 25 was synthesized from Intermediate 7 and Intermediate 8 (obtained according to the method described in Zh. Org. Khim., 13, pp. 1189-1192, 1977) in a similar method to that for Compound 23 (15.0 g).
- mice Tumor tissue pieces of mouse colon carcinoma (colon 26 carcinoma) were subcutaneously grafted to the left breast of BALB/c nude mice (5 weeks old, Clea Japan, Inc.). Ten days later when the tumor grew to a diameter of about 8 mm, the mice were subjected to the test.
- a fluorescence excitation light source a titanium sapphire laser was used.
- the test mice were uniformly exposed to the laser light using a ring type light guide (Sumita Optical Glass Co.) wherein dispersion of irradiation was within 10%. The irradiation power output was adjusted so that the power was about 40 ⁇ W/cm 2 near skin surface of the mice.
- the fluorescence was excited at the maximum excitation wavelength of each compound and fluorescence emission from the mice was detected and photographed through a short wavelength cutoff filter (IR84, IR8, IR88, Fuji Photo Film CO., LTD.) with CCD camera (C4880, Hamamatsu Photonics K.K).
- the cutoff filter was selected to fit the excitation wavelength of the compound.
- the exposure time was adjusted depending on the fluorescence intensity of each compound.
- Compound 2 as a test compound (0.5 mg/ml) was dissolved in physiological saline or phosphate buffer (pH7.4) and administered to the mice via a tail vein at the dose of 5.0 mg/Kg.
- mice were anesthetized with diethyl ether and fluorescent light images of the entire body of the mice was photographed.
- ICG 5 mg/kg, i.v.
- Compound A the following compound
- Compound 2 gave clear images of tumors at a shorter time after the administration as compared to the reference compounds. The position of tumor was not clear within 1 hour after the administration of the reference compounds. Whilst, Compound 2 successfully gave clear images of the tumor at 10 to 30 minutes after the administration and revealed to be highly effective as a fluorescent contrast agent ( FIG. 1 ).
- Tumor bearing mice were prepared in the same manner as Test Example 1, and conditions for irradiation was the same as those explained in Test Example 1.
- Compound 5, Compound 7, and Compound 10 were used as test compounds.
- Each of the test compounds (0.5 mg/ml) was dissolved in physiological saline or phosphate buffer (pH 7.4) and administered to the mice via a tail vein at the dose of 5.0 mg/Kg.
- the following compound (Compound B, 5 mg/kg, i.v.) was administered to the mice.
- Light was generated using a tunable, pulsed, solid state laser system consisting of an optical parametric oscillator (OPO) pumped by the third harmonic of a Nd:Yag laser (Coherent Inc.).
- OPO optical parametric oscillator
- the dye-specific fluorescence exitance was imaged using a filter combination (Corion) and an intensified CCD camera (Roper Scientific.) at different times after dye administration ( FIG. 4 ). Fluorescence imagings were taken before administration, and min, 10 min 30 min, 60 min, 2 hours, 4 hours, 24 hours after intravenous dye administration via the lateral tail venous at a standard dose of 5 mg/kg.
- the near infrared fluorescence contrast agent of the present invention can emit near infrared fluorescence by an excitation light.
- the near infrared fluorescence is superior in permeability through biological tissues, and therefore, the agent enables the detection of a lesion in a deep part of a living body.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- General Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Indole Compounds (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Plural Heterocyclic Compounds (AREA)
- Investigating Materials By The Use Of Optical Means Adapted For Particular Applications (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Endoscopes (AREA)
Abstract
A near infrared fluorescent contrast agent which is excellent in permeability in a living tissue and enables specific imaging of tumor and/or blood vessel, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R7, and R8 represent a C1-C10 alkyl group or the like; R3, R4, R5, R6, R9, R10, R11, and R12 represent a hydrogen atom, a C1-C6 alkyl group, an aryl group or the like; X1 and X2 represent a C1-C15 alkyl group or an aryl group and X1 and X2 in total have 0 to 4 carboxyl groups; m1, m2, and m3 represents 0 or 1; L1 to L7 independently represent a methine group; M represents a hydrogen atom, a metal, or a quaternary ammonium salt; and n represents an integer of 1 to 7 necessary for neutralizing charge.
Description
- The present invention relates to a near infrared fluorescent contrast agent, and a method of fluorescence imaging using said near infrared fluorescent contract agent.
- In treating disease, it is important to detect morphological and functional changes caused by the disease in the living body at an early stage of the disease. Especially for treatment of a cancer, to know the site and size of the tumor beforehand is an extremely important means to determine strategies and protocols for future treatment. Methods so far applied include biopsy by puncture and the like, as well as imaging diagnosis such as X-ray imaging, MRI, ultrasound imaging and the like. Biopsy is an effective means for definitive diagnosis, however, it places great burden on a patient to be diagnosed, and also is not suitable for tracing changes with time in lesions. X-ray imaging and MRI inevitably cause exposure of a patient to be diagnosed with irradiation or electromagnetic wave. In addition, conventional imaging diagnoses as mentioned above require complicated operation and a prolonged time for measurement and diagnosis. A large size of an apparatus also makes it difficult to apply these methods during surgical operation.
- One of reported image diagnoses includes fluorescence imaging (Lipspn R. L. et al., J. Natl. Cancer Inst., 26, 1-11 (1961)). This method employs a substance as a contrast agent that emits fluorescence upon exposure to an excitation light having a specific wavelength. The method comprises the step of exposing a body with an excitation light from outside the body and then detecting fluorescence emitted from the fluorescent contrast agent in vivo.
- An example of the fluorescent contrast agent include, for example, a porphyrin compound that accumulates in tumor and is used for photodynamic therapy (PDT), e.g., haematoporphyrin. Other examples include photophyrin and benzoporphyrin (see, Lipspn R. L. et al., supra, Meng T. S. et al., SPIE, 1641, 90-98 (1992), WO84/04665 an the like). However, these compounds have phototoxicity since they are originally used for PDT (PDT requires such property), and accordingly, these compounds are not desirable as diagnostic agents.
- Retinal circulatory microangiography using a known fluorescent dye, such as fluorescein, fluorescamine, and riboflabin, has been known (U.S. Pat. No. 4,945,239). However, these fluorescent dyes emit fluorescence in a region of a visible light of 400-600 nm which only achieves low transmission through living tissue, and consequently, detection of a lesion in a deeper part of a body is almost impossible.
- Cyanine compounds including indocyanine green (hereinafter abbreviated as “ICG”), which are used to determine liver function and cardiac output, have been also reported to be useful as fluorescent contrast agents (Haglund M. M. et al., Neurosurgery, 35, 930 (1994), Li, X. et al., SPIE, 2389, 789-797 (1995)). Cyanine compounds have absorbance in a near infrared light region (700 to 1300 nm).
- Near infrared light has a high transmission property through living tissues and can pass through the skull of about 10 cm, and from these reasons, said light has been focused recently in the filed of clinical medicine. For example, the optical CT technique (a CT technique using optical transmission of a medium) has become focused as a new technology in the clinical flied, because near infrared light can pass through a living body and, oxygen concentration and circulation in vivo can be detected by using a light within this region.
- The cyanine compound emits fluorescence in the near infrared region, a light of which region has excellent permeability in living tissues as explained above, and accordingly a use as a fluorescent contrast agent has been proposed. Various cyanine compounds have been developed in recent years, and approaches for use as fluorescent contrast agents have been made (WO96/17629, WP97/13490 and the like). However, an agent having a satisfactory distinguishing ability of a lesion from normal tissues, i.e., an agent having a satisfactory selectively to a target site to be imaged, has not yet been available.
- An object of the present invention is to provide a fluorescent contrast agent which emits fluorescence in the near infrared region that is excellent in permeability in a living tissue, and enables specific imaging of tumor and/or blood vessel. Another object of the present invention is to provide a method of fluorescence imaging using said near infrared fluorescent contract agent.
- The inventors of the present invention conducted various studies to achieve the foregoing objects. As a result, by introducing carboxylic acid or an aryl group to cyanine dyes, they succeeded in providing a fluorescent contrast agent having high tumor selectivity. They also succeeded in establishing a method for fluorescence imaging by using said contrast agent. The present invention was achieved on the basis of the above findings.
- The present invention thus provides a near infrared fluorescent contrast agent comprising a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof:
- wherein R1, R2, R7, and R8 independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted aryl group, and R1 and R2 and/or R7 and R8 may bind to each other to form a ring; R3, R4, R5, R6, R9, R10, R11, and R12 independently represent a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a halogen atom, cyano group, carboxyl group, or sulfo group, and R3, R4, R5, R6, R9, R10, R11, and R12 may bind to each other to form a ring; X1 and X2 independently represent a substituted or unsubstituted C1-C15 alkyl group or a substituted or unsubstituted aryl group and X1 and X2 in total have 0 to 4 carboxyl groups, provided that when the number of the carboxyl group is 0 or 1, each of X1 and X2 is a C1-C5 carboxyalkyl group or a sulfoalkyl group and at least one of R3, R4, R5, R6, R9, R10, R11, and R12 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; m1 represents 0 or 1; m2 represents 0 or 1; m3 represents 0 or 1; L1, L2, L3, L4, L5, L6, and L7 independently represent a substituted or unsubstituted methine group, provided that when two or more of the methine groups have substituents, the substituent may bind to each other to form a ring, provided that when each of X1 and X2 has one carboxyl group, each of X1 and X2 is carboxyl group-substituted hydrocarbon group and at least one of the methine groups represented by L1, L2, L3, L4, L5, L6, and L7 is a substituted methine group and R4 and R10 represent a sulfo group; M represents a hydrogen atom, a metal, or a quaternary ammonium salt; and n represents an integer of 1 to 7 necessary for neutralizing charge.
- According to a preferred embodiment of the above invention, each of m1, m2, and m3 is simultaneously 1, and X1 is a group represented by the following formula (i):
- wherein Y1 and Y2 independently represent a substituted or unsubstituted divalent linking group.
- According to a more preferred embodiment, X1 and X2 independently represent a group represented by the following formula (i):
- wherein Y1 and Y2 independently represent a substituted or unsubstituted a divalent bond.
- According to further preferred embodiment, at least one of R3, R4, R5, R6, R9, R10, R11, and R12 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and according to still further preferred embodiment, at least one of R4, R5, R10, and R11 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and each of X1 and X2 is independently a C1-C6 carboxylalkyl group or a sulfoalkyl group.
- According to another preferred embodiment, X1 and X2 independently represent a group represented by the following formula:
- wherein Y3 represents a C1-C10 hydrocarbon group and at least one of the methine groups represented by L1, L2, L3, L4, L5, L6, and L7 is a substituted methine group and each of R4 and R10 is a sulfo group.
- Preferably, the number of sulfo group in a molecule is two or less.
- According to further preferred embodiment, Y1 represents —(CH2)pCONH—wherein p represents an integer of 1 to 4 and Y2 represents —(CH2)— or (CH2)2—.
- The aforementioned near infrared fluorescent contrast agent may preferably be used for tumor imaging or angiography.
- From another aspect, provided is a method of fluorescence imaging which comprises the steps of introducing the aforementioned near infrared fluorescent contrast agent into a living body, exposing said body to an excitation light, and detecting near infrared fluorescence from the contrast agent.
-
FIG. 1 is a photograph showing the results of fluorescence imaging at given times after the administration ofCompound 2 of the present invention. -
FIG. 2 is a photograph showing the results of fluorescence imaging at given times after the administration of ICG as a reference. -
FIG. 3 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound A as a reference. -
FIG. 4 is a schematic view of experimental set up for fluorescence imaging in Test Example 2. In the figure, SHG represents second harmonic generation; THG represents third harmonic generation; and OPO represents optical parametric oscillator. -
FIG. 5 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 5 of the present invention. -
FIG. 6 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 7 of the present invention. -
FIG. 7 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound 10 of the present invention. -
FIG. 8 is a photograph showing the results of fluorescence imaging at given times after the administration of Compound B as a reference. - The C1-C10 alkyl group represented by R1, R2, R7, and R8 may be linear, branched, cyclic, or a combination thereof (an alkyl group and an alkyl moiety of a functional group containing the alkyl moiety have the same meaning in the specification unless otherwise specifically mentioned). As the unsubstituted alkyl group, for example, methyl group, ethyl group, propyl group, butyl group, and hexyl group can be used. The number, kind, or position of substituents on the substituted alkyl group are not particularly limited. As the substituted alkyl, for example, sulfoalkyl group, carboxylalkyl group, hydroxyalkyl group, alkoxyalkyl group, aminoalkyl group, halogenated alkyl group, cyanoalkyl group, aryl-substituted alkyl group, heteroaryl-substituted alkyl group and the like can be used.
- The aryl group represented by R1, R2, R7, and R8 may be either a monocyclic ring or a condensed ring, for example, a C6-C14 aryl group, preferably C6-C10 aryl group can be used (an aryl group and an aryl moiety of a functional group containing the aryl moiety have the same meaning unless otherwise specifically mentioned). As the aryl group, preferably phenyl group or naphthyl group, more preferably phenyl group may used. As the substituted aryl group, sulfophenyl group, hydroxyphenyl group, aminophenyl group can be used.
- Further, R1 and R2, R7 and R8 may bind to each other to form a ring. Examples of the ring formed include, for example, cyclopentyl ring, cyclohexyl ring and the like. R1, R2, R7, and R8 are preferably methyl group or ethyl group, more preferably methyl group.
- R3, R4, R5, R6, R9, R10, R11, and R12 independently represent a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a halogen atom, cyano group, carboxyl group, or sulfo group, and two adjacent groups selected from the group consisting of R3, R4, R5, and R6 or those selected from the group consisting of R9, R10, R11, and R12 may independently bind to each other to form a ring. The ring formed may be saturated or unsaturated, and may be a hydrocarbon ring or a heterocyclic ring. For example, R3 and R4, R4 and R5, R5 and R6, R9 and R10, R10 and R11, or R11 and R12 can bind to each other to form a benzene ring or an aromatic heterocyclic ring such as pyridine ring. Preferred examples include a benzene ring formed by binding of R3 and R4, or R9 and R10.
- As the aryl group represented by R3, R4, R5, R6, R9, R10, R11, and R12, for example, phenyl group or naphthyl, group can be used, as the heteroaryl group, for example, thienyl group, benzothienyl group, furyl group, benzofuryl group, pyrrolyl group, imidazolyl group, or quinolyl group can be used. One to four optional substituents may be present on the aryl group and the heteroaryl group. The position of the substituents is not limited, and when two or more substituents are present, they may be same or different. As such substituents, for example, hydroxyl group, a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C6 alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group; C1-C6 halogenated alkyl group such as trifluoromethyl group; a C1-C6 alkoxyl group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group; a C1-C6 alkylenedioxy group such as methylenedioxy group, ethylenedioxy group; carboxyl group; a C1-C6 alkoxycarbonyl group; an unsubstituted amino group; a C1-C6 alkyl-substituted amino group such as methylamino group, dimethylamino group, ethylamino group; a sulfo group; or a cyano group and the like can be used.
- X1 and X2 independently represent a substituted or unsubstituted C1-C15 alkyl group or a substituted or unsubstituted aryl group, and X1 and X2 have one to four carboxyl groups in total of X1 and X2. As the unsubstituted alkyl represented by X1 and X2, for example, methyl group, ethyl group, propyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 2-methylpropyl group, or 1,1-dimethylpropyl group can be used. The alkyl group may be linear, branched, cyclic, or a combination thereof, and a linear or branched alkyl group is preferred.
- As the substituted alkyl group represented by X1 and X2, for example, a sulfoalkyl group (such as 2-sulfoethyl group, 3-sulfopropyl group, 3-methyl-3-sulfopropyl group, 4-sulfobutyl group and the like), a carboxyalkyl group (such as 1-carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the like), a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a halogenated alkyl group, a cyanoalkyl group, a heteroaryl-substituted alkyl group, an aryl group, or a heteroaryl group can be used. The alkyl moiety of these groups is the same as those defined in the above-mentioned unsubstituted alkyl group. As the substituted or unsubstituted aryl group represented by R1, R2, R7, and R8, phenyl group, sulfophenyl group, hydroxyphenyl group, or aminophenyl group can be used.
- When the number of carboxyl group of X1 and X2 is 0 or 1, a C1-C5 carboxyalkyl group or a sulfoalkyl group can be used as the X1 and X2.
- As the divalent liking group represented by Y1 and Y2, for example, a substituted or unsubstituted C1-C6 alkylene group such as methylene group, ethylene group, n-butylene group, methylpropylene group, or phenylene group can be used. As another example, a linking group represented by the following formula can be used:
- wherein q represents an integer of 1 to 4, and the symbol “−” represents a bonding position. These hydrocarbon groups may have substituents and may contain one or more hetero atoms. For example, they may contain an ether bond, a thioether bond, a disulfide bond, an amide bond, an ester bond, a sulfonamide bond, or a sulfoester bond.
- As the divalent linking group represented by Y1 and Y2, for example, a bond represented by the following formula can also be used:
- wherein p represents an integer of 1 to 4, and the symbol “−” represents a bonding position. An preferred example of Y1 include a linking group represented by the following formula:
- wherein p represents an integer of 1 to 4. Most preferably, Y1 is —(CH2)p—CO—NH— (wherein p represents an integer of 1 to 4). Preferred examples of Y2 include methylene group or ethylene group.
- L1, L2, L3, L4, L5, L6, and L7 independently represent a substituted or unsubstituted methine group, wherein m1, m2, and m3 independently represent 0 or 1. It is preferred that each of m1, m2, and m3 is simultaneously 1. Examples of the substituent on the methine group include a substituted or unsubstituted alkyl group, a halogen atom, a substituted or unsubstituted aryl group, or a lower alkoxy group and the like. An specific examples of the substituted aryl group includes 4-chlorophenyl group and the like. The lower alkoxy group may preferably be a C1-C6 alkoxy group which may be linear or branched. Specific examples include methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, pentyloxy group and the like, and methoxy group or ethoxy group is preferred. As the substituent of the methine group, methyl group or phenyl group can preferably be used.
- When the methine groups selected from L1, L2, L3, L4, L5, L6, and L7 are substituted, the substituents on the methine groups may bind to each other to form a ring. Preferably, the substituents on the methine groups may bind to form a ring containing three successive methine group selected from the group consisting of L1, L2, L3, L4, L5, L6, and L7. As an example wherein the substituents on the methine groups bind to each other to form a ring containing three successive methine group selected from the group of L1, L2, L3, L4, L5, L6, and L7 include, for example, a compound wherein 4,4-dimethylcyclohexene ring is formed to contain L3, L4, and L5. A particularly preferred example of a partial structure in which a conjugated methine chain formed by methine groups selected from the group of L1, L2, L3, L4, L5, L6, and L7 contains a ring includes a group represented by the following general formula (a):
- wherein Z represents a nonmetallic atom group necessary for forming a 5- or 6-membered ring, and A represents a hydrogen atom or a monovalent group.
- Examples of the nonmetallic atom group necessary for forming a 5- to 10-membered ring represented by Z include, for example, a carbon atom, a nitrogen atom, an oxygen atom, a hydrogen atom, a sulfur atom, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) and the like. Examples of the 5- or 6-membered ring in the partial structure represented by the general formula (a) include, for example, cyclopentene ring, cyclohexene ring, and 4,4-dimethylhexene ring, and cyclopentene ring or cyclohexene ring is preferred.
- Examples of the monovalent group represented by A include, for example, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkylcarbonyloxy group (such as acetoxy group), a substituted or unsubstituted alkylthio group, a substituted or unsubstituted arylthio group, cyano group, nitro group, a halogen atom and the like.
- Specific examples of the aralkyl group represented by A include benzyl group, 2-phenylethyl group, 3-phenylpropyl and the like. Examples of the substituent of the aralkyl group include, for example, sulfo group, carboxyl group, hydroxyl group, a substituted or unsubstituted alkyl, group, an alkoxy group, a halogen atom and the like. Specific examples of the substituted amino group represented by A include, for example, an alkylamino group (such as methylamino group, ethylamino group and the like), a dialkylamino group (such as dimethyl amino group, diethylamino group and the like), phenylamino group, diphenylamino group, methylphenylamino group, a cyclic amino group (such as morpholino group, imidazolidino group, ethoxycarbonylpiperadino group and the like). When the substituted amino group has a further substituent, sulfo group, carboxyl group and the like can be used as the substituent. Specific examples of the arylthio group represented by A include phenylthio group, naphthylthio group and the like, and examples of a substituent of the arylthio group include sulfo group, carboxyl group and the like.
- Examples of the monovalent group represented by A include phenylamino group, diphenylamino group, ethoxycarbonyl piperazino group, arylthio group and the like.
- Y represents a nonmetallic atom necessary for forming a 5- to 10-membered heterocyclic ring, preferably, a 5- or 6-membered heterocyclic ring (the heterocyclic ring may be a condensed ring). Examples of the 5- to 10-membered heterocyclic ring formed by Y include the following rings: thiazole ring (such as thiazole, 4-methylthiazole and the like), benzothiazole ring (such as benzothiazole, 4-chlorobenzothiazole and the like), naphthothiazole ring (such as naphtho[2,1-d]-thiazole, naphtho[1,2-d]thiazole and the like), thiazoline ring (such as thiazoline, 4-methylthiaazoline and the like), oxazole ring (such as oxazole, 4-nitrooxazole and the like), benzoxazole (such as benzoxazole, 4-chrolobenzoxazole and the like), naphthoxazole (such as naphtho[2,1-d]oxazole, naphtho[1,2-d]oxazole and the like), selenazole ring (such as selenazole, 4-phenyl selenazole and the like), benzoselenazole ring (such as benzoselenazole, 4-chrolobenzoselenazole), naphtoselenazole ring (such as naphtho[2,1-d]selenazole, naphtho[1,2-d]selenazole and the like), 3,3-dialkylindolenine ring (such as 3,3-dinitroindolenine, 3,3-diethylindolenine, 3,3-dimethyl-5-nitroindolenine and the like), imidazole ring (such as 1-alkylimidazole, 1-alkyl-4-phenylimidazole and the like), pyridine ring (such as 2-pyridine, 5-methyl-2-pyridine and the like), quinoline ring (such as 2-quinoline, 3-methyl-2-quinoline and the like), imidazo[4,5-b]quinoxaline ring (such as 1,3-diethylimidazo[4,5-b]quinoxaline and the like) and the like. Preferred examples of the 5- to 10-membered heterocyclic ring formed by Y include 3,3-dialkylindolenine ring.
- M represents hydrogen atom, a metal, quaternary ammonium salt, or other pharmaceutically acceptable salts. The “pharmaceutically acceptable salts” may be any salt which can form nontoxic salts with the compound represented by the general formula [I]. Examples include, for example, alkaline metal salt such as a sodium salt, a potassium salt and the like; alkaline-earth metal salt such as a magnesium salt, a calcium salt and the like; organic ammonium salt such as a ammonium salt, a triethyl ammonium salt, tributyl ammonium salt, pyridinium salt and the like; salt of amino acid such as lysine salt, arginine salt and the like. Particularly preferred is a sodium salt with a reduced toxicity to a living body.
- The compound of the present invention may have one or more asymmetric carbon atoms depending on the kind of substituents. Sulfur atoms may act as asymmetric center. Any optical isomers in an optically pure form based on one or more asymmetric carbon atoms, any mixture of the above optical isomers, racemates, diastereomers based on two or more asymmetric carbon atoms, any mixture of the above diastereomers and the like fall within the scope of the present invention.
- Specific examples of the compound of the present invention are shown below. However, the scope of the present invention is not limited by the following compounds.
- The cyanine dye represented by the formula [I] or [II] can be synthesized according to known preparation methods of cyanine dye compounds, for example, those disclosed in the Cyanine Dyes and Related Compounds, F. M. Hamer, John Wiley and Sons, New York, 1964, Cytometry, 11, 416-430 (1990), Cytometry, 12, 723-730 (1990), Bioconjugate Chem, 4, 105-111 (1993), Anal. Biochem., 217, 197-204 (1994), Tetrahedron, 45, 4845-4866 (1989), EP-A-0591820A1, EP-A-0580145A1 and the like. Alternatively, they can be semisynthesized from a commercially available cyanine dye compound by known methods. More specifically, they can be synthesized by reacting a diaryl compound with a heterocyclic quaternary salt.
- The methods for preparing the cyanine dye compounds represented by the above formula [I] or [II] are not particularly limited, and the compounds can be synthesized by various synthetic routes. Specific preparations of typical compounds of the present invention are disclosed in the Examples of the specification. Accordingly, one of ordinary skill in the art can prepare the cyanine dye compounds that falls within the scope of the above general formulas by referring to the methods described in the Examples, and if necessary, by adding appropriate alteration or modification to the methods and by appropriately choosing starting materials and reagents. For the preparation, a reaction selected from various reactions such as condensation, addition, oxidation, reduction and the like may be employed alone or in combination. These reactions are explained in detail in the literature. For example, various methods or material compounds described as unit synthetic operations in “Jikken Kagaku Kouza” (published by Maruzen, Ltd., each separate volume contained in the first to forth comprehensive edition is available) can be suitably used. In addition, syntheses of the compounds of the present invention are specifically described in the specification of PCT/JP01/06689, whose disclosures are herein incorporated by reference.
- For example, where the above defined functional groups may change in a reaction step or they are not suitable to conduct a reaction step in the preparation, a desirable step can be sometimes conducted efficiently by utilizing various methods which are conventionally used in the filed of organic synthetic chemistry, for example, means for protection or deprotection of functional groups, or treatments such as oxidation, reduction, hydrolysis and the like. Synthetic intermediate compounds and the target compounds in the above steps can be isolated and purified by conventional purification methods used in organic synthetic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography and the like. The synthetic intermediate products can be used in the next reaction without isolation.
- As the active ingredient of the near infrared fluorescent contrast agent of the present invention, the compound represented by the general formula [I] in or [II] or a salt thereof may be used alone or in combination. More specifically, the active ingredient may be contained in the contrast agent in a form of a suspension or a solution in a solvent such as injectable distilled water, physiological saline, Ringer's solution and the like. Additives such as pharmaceutically acceptable carrier, excipients and the like may also be formulated, if desired. Examples of these additives include substances such as pharmaceutically acceptable electrolytic solutions, buffering solutions, detergents, and substances for adjusting osmotic pressure, substances for improving stability or solubility such as cyclodextrin, liposome and the like. Any additives ordinarily available in the art may be used. The near infrared fluorescent contrast agent of the present invention is preferably synthesized through sterilization processes when used as a medicament for clinical application.
- The contract agent can be administered to a living body by injection, spraying, or topical application such as intravascular application (venous, arterial), oral application, intraperitoneal application, percutaneous application, subcutaneous application, intracystical application, or intrabronchial application. Preferably, the contrast agent may be administered into blood vessels in the form of an aqueous solution, an emulsion or a suspension.
- The dose of the near infrared fluorescent contrast agent of the present invention is not particularly limited insofar as the dose enables detection of a site to be diagnosed. The dose may appropriately be increased or decreased depending on the type of the compound to be used that emits near infrared fluorescence, the age, body weight and a target organ of a subjects to be administered and the like. Typically, the dose as the weight of the compound may be 0.1 to 100 mg/kg body weight, preferably 0.5 to 20 mg/kg body weight.
- The contrast agent of the present invention may also be appropriately used for various animals other than human. A formulation for administration, the route of administration, a dose and the like may be appropriately chosen depending on the body weight and conditions of the target animals.
- The compounds of the present invention represented by the above formula [I] and [II] have property to highly accumulated in tumor tissues. Utilizing said property, the present invention also provides the fluorescent contrast agent which enables specific imaging of a tumor tissue. In addition, the class of the compounds of the present invention have long-term retention in blood vessels, and therefore, the fluorescent contrast agent of the present invention is also useful for angiography.
- The method for fluorescence imaging of the present invention is characterized by the use of the near infrared fluorescent contrast agent of the present invention. The method for imaging can be carried out by one of ordinary skill in the art according to known methods, and each of parameters such as excitation wavelength and fluorescence wavelength to be detected may appropriately be determined to achieve optimal imaging and evaluation, depending on the kind of near infrared fluorescence contrast agent to be administered and a subject to be administered. The period of time from administration of the near infrared fluorescent contrast agent of the present invention to the start of fluorescence imaging according to the present invention may vary depending on the kind of the near infrared fluorescent contrast agent to be used and a subject to be administered. For example, when the contrast agent comprising a compound of the formula [I] or formula [II] is administered for tumor imaging, a lapse time may be about 10 minutes to 24 hours after administration. When the lapse time is too short, fluorescence from every site may be still too intense and the target site is not distinguishable from other sites, and when the lapse time is too long, the contrast agent may be excreted from the body. When imaging of blood vessel is desired, the compound of the formula [I] or formula [II] is detected immediately after administration or in about 30 minutes after the administration.
- For example, the fluorescence imaging can be conducted by the following steps. A near infrared fluorescent contrast agent of the present invention is administered to a subject to be diagnosed, and then the subject is exposed to an excitation light using an apparatus generating excitation light. Then, fluorescence from the near infrared fluorescent contrast agent, which is generated by the excitation light, is detected by using a fluorescence detector. The wavelength for excitation varies depending on the type of the near infrared fluorescent contrast agent to be used, and is not limited as long as the compounds efficiently emits fluorescence in the near infrared region. Preferably, a near infrared light having superior bio-permeability may be used. The wavelength of the near infrared fluorescence to be detected also varies depending on the contrast agent to be used. In general, an excitation light having a wavelength of 600 to 1000 nm, preferably 700 to 850 nm, may be used and near infrared fluorescence having a wavelength of 700 to 1000 nm, preferably, 750 to 900 nm, may be detected. As the apparatus for generating the excitation light, a conventional excitation light source such as various lasers (e.g., ion lased, dye laser and semiconductor laser), halogen light source, xenon light source and the like may be used. Various optical filters may be used to obtain optimal excitation wavelength, if desired. For detection of fluorescence, various optical filters may be used for selection of the fluorescence generated from the near infrared fluorescent contrast agent.
- The detected fluorescence is data-processed as fluorescence information to construct fluorescence images to be recorded. Examples of the method for preparation of fluorescence images include, for example, a method comprising the step of irradiating the target tissue in a wide range, detecting fluorescence with a CCD camera, and then image-processing the fluorescence information obtained; a method using an optical CT device; a method using an endoscope; or a method using fundus oculi camera and the like.
- According to the fluorescence imaging method of the present invention, systemic diseases, tumors, blood vessels and the like can be visualized without damaging a living body.
- The present invention will be more specifically explained by referring to synthetic examples and a test example. However, the scope of the present invention is not limited to the following examples. In the examples, the serial numbers of the compounds correspond to that of the compounds listed in the above with chemical structures.
- Synthetic route of
Compound 1 is shown below. - The starting material 1 (20.9 g, 0.1 mol), 2-bromopropinic acid (23.0 g, 0.15 mol), and o-dichlorobenzene (20 ml) were heated and stirred at 140° C. for 2 hours. After the reaction was completed, the reaction mixture was added with acetone (200 ml) and cooled to room temperature, and then the resultant crystal was filtrated to obtain Intermediate 1 (20.3 g, yield: 56%)
- The
Intermediate 1 obtained above (10.0 g, 28 mmol) and 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene hydrochloride (3.9 g, 14 mmol) were dissolved in acetonitrile (70 ml) and water (11 ml), and the resulting solution was added with triethylamine (8.4 g, 91 mmol) and acetic anhydride (8.5 g, 91 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was added to 0.1N hydrochloric acid (900 ml) dropwise and the crystals precipitated were filtrated. The crystal was purified by column chromatography (eluent: methylene chloride:methanol=95:5˜90:10) to obtain Intermediate 2 (2.1 g, yield: 12%) - The
Intermediate 2 obtained above (21.0 g, 1.5 mmol), L-aspartic acid-di-t-butylester monohydrate (1.3 g, 4.5 mmol), 4-dimethylaminopyridine (40 mg, 0.3 mmol) were dissolved in methylene chloride (50 ml) and the solution was cooled on ice. The resultant solution was added with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) (700 mg, 4 mmol) and triethylamine (340 mg, 3 mmol), and stirred at 4° C. for overnight. The reaction mixture was added with methylene chloride (200 ml) and 1N hydrochloric acid (200 ml), and then the methylene chloride layer is extracted and washed with saturated sodium chloride solution (200 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography (eluent: ethyl acetate:methanol=95:5 to 80:20) to obtain Intermediate 3 (1.1 g, yield: 64%) - Intermediate 3 (500 mg, 0.5 mmol) was dissolved in trifluoroacetic acid (5 ml) and reacted at 4° C. for overnight, and then trifluoroacetic acid was evaporated under reduced pressure. The resulting residue was added with water (50 ml) and then the resulting crystals were collected by filtration and washed with water and ethyl acetate to obtain Compound 1 (390 mg, yield: 90%).
-
Compound 1 was purified by column chromatography using Sephadex (LH-20, Pharmacia) (eluent: methanol) to obtainCompound 2. -
Compound 1 was applied to an ion exchange resin column CR 11 (Mitsubishi Chemical, Co., Ltd.) to obtain Compound 3. - 1H-NMR (CD3OD) δ 1.98 (s, 12H), 2.70 (d, J=7.2 Hz, 4H), 2.80 (t, J=7.2 Hz, 4H), 3.30 (MeOH), 4.50 (t, J=7.2 Hz, 4H), 4.60 (t, J=7.2 Hz, 2H), 4.80 (H2O), 6.40 (d, J=13.2 Hz, 2H), 6.63 (dd, J=13.2, 13.2 Hz, 2H), 7.40-7.50 (m, 2H), 7.58-7.66 (m, 5H), 7.95-8.07 (m, 6H), 8.20 (d, J=7.2 Hz, 2H)
- 1H-NMR (CD3OD) δ 1.99 (s, 12H), 2.72 (d, J=7.2 Hz, 4H), 2.80 (t, J=7.2 Hz, 4H), 3.30 (MeOH), 4.50 (t, J=7.2 Hz, 4H), 4.60 (t, J=7.2 Hz, 2H), 4.80 (H2O), 6.38 (d, J=13.2 Hz, 2H), 6.61 (dd, J=13.2, 13.2 Hz, 2H), 7.40-7.50 (m, 2H), 7.58-7.67 (m, 5H), 7.96-8.07 (m, 6H), 8.21 (d, J=7.2 Hz, 2H)
- 1H-NMR (CD3OD) δ 1.98 (s, 12H), 2.56-2.65 (m, 4H), 2.75-2.85 (m, 4H), 3.30 (MeOH), 4.45-4.50 (m, 4H), 4.80 (H2O), 6.20 (d, J=13.2 Hz, 2H), 6.65 (dc, J=13.2, 13.2 Hz, 2H), 7.40-7.50 (m, 2H), 7.58-7.70 (m, 5H), 7.95-8.07 (m, 6H), 8.20 (d, J=7.2 Hz, 2H)
- Compound 5 was synthesized from
Intermediate Compound 1. - 1H-NMR (CD3OD) δ 2.00 (s, 12H), 2.44 (s, 3H), 2.73 (d, J=7.2 Hz, 4H), 2.82 (t, J=7.2 Hz, 4H), 3.31 (MeOH), 4.50 (t, J=7.2 Hz, 4H), 4.69 (t, J=7.2 Hz, 2H), 4.88 (H2O), 6.41 (d, J=13.2 Hz, 2H), 6.65 (d, J=13.2 Hz, 2H), 7.43-7.50 (m, 2H), 7.58-7.67 (m, 4H), 7.95-8.05 (m, 4H), 8.10-8.27 (m, 4H)
- Compound 6 was synthesized from
Intermediate Compound 1 except that L-glutamic acid-di-t-butylester monohydrate was used instead of L-aspartic acid-di-t-butylester monohydrate. - 1H-NMR (CD3OD) δ 1.80-2.15 (m, 4H), 2.01 (s, 12H), 2.28 (t, J=7.2 Hz, 4H), 2.44 (s, 3H), 2.82 (t, J=7.2 Hz, 4H), 3.31 (MeOH), 4.40-4.50 (m, 2H), 4.51 (t, J=7.2 Hz, 4H), 4.88 (H2O), 6.42 (d, J=13.2 Hz, 2H), 6.65 (d, J=13.2 Hz, 2H), 7.42-7.50 (m, 2H), 7.57-7.67 (m, 4H), 7.95-8.05 (m, 4H), 8.10-8.27 (m, 4H)
- Compound 7 was synthesized from 2,3,3-trimethylindolenine in a similar manner to that for
Compound 1. - 1H-NMR (CD3OD) δ 1.70 (s, 12H), 2.05-2.13 (m, 4H), 2.55 (t, J=7.2 Hz, 4H), 2.78-2.92 (m, 4H), 3.30 (MeOH), 4.10 (t, J=7.2 Hz, 4H), 4.89 (H2O), 6.45 (d, J=138.2 Hz, 2H), 6.50 (J=13.2 Hz, 2H), 7.29-7.50 (m, 8H), 7.92 (dd, J=13.2, 13.2 Hz, 2H)
- Compound 8 was synthesized from 2,3,3-trimethylindolenine in a similar manner to that for
Compound 1 except that 1,7-diaza-5-methyl-1,7-diphenyl-1,3,5-heptatriene monohydrochloride was used instead of 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrate. - 1H-NMR (CD3OD) δ 1.70 (s, 12H), 1.72-1.90 (m, 8H), 2.35-2.39 (m, 7H), 2.73-2.84 (m, 4H), 3.30 (MeOH), 4.08 (t, J=7.2 Hz, 4H), 4.66 (t, J=7.2 Hz, 2H), 4.89 (H2O), 6.33 (d, J=13.2 Hz, 2H), 6.63 (d, J=13.2 Hz, 2H), 7.18-7.50 (m, 5H), 8.05 (dd, J=13.2, 13.2 Hz, 2H)
- Compound 9 was synthesized from 6-phenyl-2,3,3-trimethylindolenine (synthesized by a method described in the specification of the U.S. Pat. No. 6,004,536) in a similar manner to that for
Compound 1. - 1H-NMR (CD3OD) δ 1.75 (s, 12H), 2.05-2.15 (m, 4H), 2.45-2.55 (m, 4H), 2.75-2.84 (m, 4H), 3.30 (MeOH), 4.20 (t, J=7.2 Hz, 4H), 4.80 (H2O), 6.38 (J=13.2 Hz, 2H), 6.62 (J=13.2 Hz, 2H), 7.43-7.70 (m, 17H), 7.95 (dd, J=13.2, 13.2 Hz, 2H)
-
Compound 10 was synthesized from 6-bromo-2,3,3-trimethyl-indolenine in a similar manner to that forCompound 1. - 1H-NMR (CD3OD) δ 1.68 (s, 12H), 2.00-2.15 (m, 4H), 2.40-2.55 (m, 4H), 2.77-2.92 (m, 4H), 3.30 (MeOH), 4.08 (t, J=7.2 Hz, 4H), 4.82 (m, 2H), 6.38 (J=13.2 Hz, 2H), 6.65 (J=13.2 Hz, 2H), 7.30-7.40 (m, 4H), 7.50-7.72 (m, 3H), 7.90-8.02 (m, 2H)
- Compound 11 was synthesized from 5-phenyl-2,3,3-trimethyl-indolenine in a similar method to that for
Compound 1. - 1H-NMR (CD3OD) δ 1.78 (s, 12H), 2.39 (s, 3H), 2.70-2.84 (m, 8H), 3.30 (MeOH), 4.30-4.46 (m, 4H), 4.60-4.68 (m, 2H), 6.39 (J=13.2 Hz, 2H), 6.66 (J=13.2 Hz, 2H), 7.30-7.48 (m, 9H), 7.56-7.72 (m, 3H), 8.05 (J=13.2 Hz, 13.2 Hz)
- Synthetic route of Compound 13 and Compound 14 is shown below.
- An intermediate compound (375 mg), which was obtained by reacting 5-sulfo-2,3,3-trimethylindolenine (prepared according to the method described in the Japanese Patent Unexamined Publication (KOKAI) No. (Hei)2-233658) and 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrochloride in methanol in the presence of triethylamine and acetic anhydride, was dissolved in 5 ml of methanol, and then applied to an column filled with cationic ion exchange resin IRC-50 (Organo, eluent: methanol). The solvent was evaporated to give the proton form of the carboxylic acid. The resulting product was dissolved in 3 ml of dimethylformamide, and the solution was added with 338 mg (1.2 mmol) of dibutyl aspartate hydrochloride, 24 mg (0.2 mmol) of dimethylaminopyridine, and 121 mg (1.2 mmol) of triethylamine, and then the mixture was cooled on ice bath. The mixture was added with 230 mg (2 mmol) of hydroxysuccinimide (HOSI) and 288 mg (1.4 mmol) of N,N-dicyclohexyl-carbodiimide (DCC), and the resulting mixture was stirred overnight. The reaction mixture was added with 200 ml of a mixed solvent of ethyl acetate/hexane (1:1) and crystals precipitated were collected by filtration. The crystals were purified by column chromatography (eluent: methylene chloride:methanol=10:1 to 2:1) to obtain diamide compound (135 mg) and monoamide compound (94 mg).
- Each of the resulting diamide compound (120 mg) and monoamide compound (60 mg) was dissolved in 2 ml of trifluoroacetic acid, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in water/methanol (1/1(v/v)) and purified by column chromatography using Sephadex (LH-20, Pharmacia, eluent: methanol). The resulting crystals were dissolved in a small volume of methanol, and the solution was added with a saturate solution of potassium acetate in methanol. Crystals precipitated were collected by filtration to obtain Compound 13 (35 mg, yield 7%) and Compound 14 (15 mg, yield 5%).
- 1H-NMR (D2O) δ 1.73 (s, 12H), 2.50-2.65 (m, 4H), 2.68-2.73 (m, 4H), 4.28-4.38 (m, 4H), 4.39-4.50 (m, 2H), 4.90 (D2O), 6.47 (d, J=13.2 Hz, 2H), 6.74 (t, J=13.2 Hz, 2H), 7.40-7.50 (m, 2H), 7.60 (t, J=13.2 Hz, 1H), 7.80-8.05 (m, 6H)
- 1H-NMR (D2O) δ 1.65 (s, 6H), 1.70 (s, OH), 2.40 (d, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 4.18-4.30 (m, 4H), 4.90 (D2O), 6.18 (d, J=13.2 Hz, 1H), 6.34 (d, J=13.2 Hz, 1H), 6.48-6.62 (m, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.30 (d, J=57.2 Hz, 1H), 7.48 (t, J=13.2 Hz, 1H), 7.68-7.95 (m, 6H)
- Synthetic route of Compound 15 is shown below.
- The starting material (41.8 g, 0.2 mol) was dissolved in conc. sulfuric acid (156 ml, 2.9 mol) and reacted at 140° C. for 1 hour, and then the mixture was cooled to 80° C. After the resulting solution was added to ice water (300 ml), a solution obtained by dissolving sodium hydroxide (96.6 g, 2.4 mol) in water (100 ml) was carefully added to the mixture. The crystals precipitated were collected by filtration and washed with water (120 ml). The resulting crude crystal was added with water (300 ml) and methanol (100 ml), and the mixture was refluxed under stirring for 30 minutes, and then cooled to room temperature. The resulting crystals were collected by filtration and washed with water (100 ml) and methanol (120 ml) to obtain Intermediate 5 (37.9 g, yield: 66%).
- Compound 15 was obtained form Intermediate 5 in a similar method to that for Compound 13.
- 1H-NMR (CD3OD) δ 2.00 (s, 12H), 2.72 (d, J=7.2 Hz, 4H), 2.82 (t, J=7.2 Hz, 4H), 3.30 (MeOH), 4.58 (t, J=7.2 Hz, 4H), 4.70 (t, J=7.2 Hz, 4H), 4.86 (H2O), 6.42 (d, J=13.2 Hz, 2H), 6.62 (dd, J=13.2, 13.2 Hz, 2H), 7.62-7.70 (m, 3H), 7.95-8.12 (m, 6H), 8.28 (d, J=7.2 Hz, 2H), 8.42 (s, 2H)
- Synthetic route of Compound 23 is shown below.
- 5-Sulfo-2,3,3-trimethylindolenine (synthesized according to the method described in Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 2-233658) (24.0 g, 0.1 mol), 2-bromopropionic acid (23.0 g, 0.15 mol) and triethylamine (10.1 g, 0.1 mol) were heated and stirred at 160° C. for 6 hours. After the reaction was completed, the reaction mixture was added with methanol (200 ml) and cooled to room temperature, and then the resulting crystals were collected by filtration to obtain Intermediate 6 (6.0 g, yield: 19.3%).
- The Intermediate 1 (3.1 g, 10 mmol) obtained above and 1,7-diaza-1,7-diphenyl-4-methyl-1,3,5-heptatriene monohydrochloride (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 8-295658) (1.5 g, 5 mmol) were dissolved in methanol (20 ml), and the resulting solution was added with triethylamine (2.5 g, 25 mmol) and acetic anhydride (4.6 g, 45 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with sodium acetate (3.3 g, 33 mmol) and stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration and washed with methanol (20 ml) to obtain Compound 23 (2.0 g, yield: 50.0%).
- 1H-NMR (D2O) a (ppm) 1.60 (s, 12H), 2.30 (s, 3H), 2.60 (t, 4H, J=7.2 Hz), 4.20 (t, 4H, J=7.2 Hz), 6.25 (d, 2H, J=14.5 Hz), 6.55 (dd, 2H, 14.5, 14.5 Hz), 7.25 (d, 2H, J=7.0 Hz), 7.70-7.80 (m, 4H), 8.00 (dd, 2H, J=14.5, 14.5 Hz)
- The synthetic route of Compound 25 and Compound 26 is shown below.
- Intermediate 7 was synthesized from 5-sulfo-2,3,3-trimethylindolenine and bromoacetic acid in a similar method to that for Intermediate 6 (16.6 g).
- Compound 25 was synthesized from Intermediate 7 and Intermediate 8 (obtained according to the method described in Zh. Org. Khim., 13, pp. 1189-1192, 1977) in a similar method to that for Compound 23 (15.0 g).
- MS (FAB-, Glycerin) m/z=844
- Compound 25 (4.2 g, 5 mmol) and triethylamine (1.0 g) was added to water (20 ml) and then the obtained solution was added with o-mercaptobenzoic acid (0.93 g, 6 mmol) and stirred at room temperature for 1 hour. The obtained mixture was added with potassium acetate (2.0 g, 20 mmol), and then added with ethanol (20 ml), the resultant crystal was filtered to obtain Compound 26 (1.3 g, yield: 27%)
- MS (FAB-, Glycerin) m/z=962
- Synthetic route of Compound 32 is shown below.
- 4-Bromophenylhydrozine monohydrochloride (73.8 g, 0.33 mmol) and 3-methyl-2-butanone (33.2 g, 0.40 mmol) were dissolved to ethanol (450 ml) and the resulting solution was added with cone sulfuric acid (7.5 ml) and refluxed under stirring for 8 hours. After the mixture was cooled to room temperature, the solution was concentrated to 100 ml under reduced pressure. To the residue, water (400 ml) and ethyl acetate (400 ml) were added, and then pH of the aqueous layer was adjusted to 7 to 8 with sodium hydroxide solution. The resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate-5:1 to 1:1) to obtain Intermediate 9 as a brown liquid (58.6 g, yield 76%)
- Intermediate 9 (4.76 g, 20 mmol) and thiophene boronic acid (3.84 g, 30 mmol) are added to dimethyl formamide (50 ml) and the resulting solution was added with palladium tetraxis phenylphosphine (1.16 g, 9 mmol) and cesium chloride (13.3 g, 40 mmol) and heated and stirred under nitrogen atmosphere at 100° C. for 4 hours. After water (200 ml) was added, the mixture was extracted with ethyl acetate (200 ml) and washed with saturated sodium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1 to 1:1) to obtain
Intermediate 10 as a brown solid (2.8 g, yield: 58%). - Intermediate 10 (1.40 g, 6 mmol) and triethylamine (0.59 g, 6 mmol) are added to dimethyl formamide (3 ml), and the mixture was added dropwise with 2-chloroethane sulfonylchloride (1.42 g, 9 mmol) under ice cooling After stirring was continued at room temperature for 30 minutes, the solution was added with a solution obtained by dissolving sodium hydroxide (0.23 g, 6 mmol) to water (2 ml) and further stirred at room temperature for 1 hour. To the mixture, ethyl acetate was added, and the upper layer was removed by decantation. The residue was dried to obtain Intermediate 11. The Intermediate 11 was used in the next reaction without further purification.
- The Intermediate 11 obtained above and 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrochloride were dissolved in methanol (5 ml) and the resulting solution was added with triethylamine (160 mg, 2 mmol) and anhydrous acetic acid (230 mg, 2 mmol), and then the mixture was stirred at room temperature for 7 hours. This mixture was added with ethyl acetate (20 ml) and the crystals precipitated were collected by filtration and washed with ethyl acetate (10 ml). This crystals were dissolved in methanol (10 ml) and then the solution was added with a saturated solution of potassium acetate in methanol (10 ml). The crystals precipitated were collected by filtration and washed with methanol (5 ml). The crystals were purified by Sephadex LH-20 (diluent:methanol) to obtain Compound 32 (15 mg, yield: 2% (from Intermediate 2).
- 1H-NMR (CD3OD) δ (ppm) 1.75 (s, 12H), 3.25 (t, 4H, J=7.2 Hz), 4.50 (t, 4H, J=7.2 Hz), 6.40 (d, 2H, J=14.5 Hz), 6.63 (dd, 2H, 14.5, 14.5 Hz), 7.07-7.12 (m, 2H), 7.33-7.45 (m, 6H), 7.53-7.75 (m, 5H), 7.96 (dd, 2H, J=14.5, 14.5 Hz)
- MS (FAB-, Glycerin) m/z=760
- The synthetic route of compound 33 is shown below.
- Intermediate 12 was synthesized from Intermediate 9 and dihydroxyphenyl borane in a similar method of that for Intermediate 10 (3.6 g, yield: 77%).
- Intermediate 12 (1.40 g, 6 mmol) and 1,4-butanesaltone (1.22 g, 9 mmol) were dissolved in dimethyl acetamide (2 ml) and the solution was stirred at 135° C. for 5 hours. The solution was added with ethyl acetate (20 ml) and cooled to room temperature, and then the crystals precipitated were filtered and washed with ethyl acetate to obtain Intermediate 13 (10 ml) (1.84 g, yield: 84%).
- Intermediate 13 (1110 mg, 3 mmol) and 1,7-diaza-1,7-diphenyl-1,3,5-heptatriene monohydrochloride (285 mg, 1 mmol) were dissolved in methanol (5 ml), and the resulting solution was added with triethylamine (480 mg, 5 mmol) and anhydrous acetic acid (670 mg, 7 mmol) and then stirred at room temperature for 7 hours. Ethyl acetate (10 ml) was added to the reaction mixture and crystals precipitated were collected by filtration and washed with ethyl acetate (10 ml). The crystals were dissolved in methanol (5 ml) and added with a saturated solution of potassium acetate in methanol (10 ml), and the crystals precipitated were filtered and washed with 5 ml. The crystal was purified by Sephadex LH-20 (diluent; methanol) to obtain Compound 33 (250 mg, yield: 30%).
- 1H-NMR (CD3OD) δ (ppm) 1.80 (s, 12H), 1.95-2.05 (m, 8H), 2.90 (t, 4H, J=7.2 Hz), 4.20 (t, 4H, J=7.2 Hz), 6.38 (d, 2H, J=14.5 Hz), 6.62 (dd, 2H, 14.5, 14.5 Hz), 7.30-7.48 (m, 8H), 7.60-7.74 (m, 9H), 7.93 (dd, 21, J=14.5, 14.5 Hz)
- MS (FAB-, Nitrobenzylalcohol) m/z=803
- Compound 34 was synthesized from Intermediate 9 and 4-methyl mercaptophenyl boronic acid in a similar method to that for Compound 33 (15 mg). 1H-NMR (CD3OD) δ (ppm) 1.68 (s, 12H), 1.95-2.10 (m, 8H), 2.50 (s, 6H), 3.00 (t, 4H, J=7.2 Hz), 4.10 (t, 4H, J=7.2 Hz), 6.30 (d, 2H, J=14.5 Hz), 6.62 (dd, 2H, 14.5, 14.5 Hz), 7.20-7.70 (m, 19H)
- Synthetic route of Compound 35 is shown below.
- 25.0 g of 3-aminodiphenyl (0.15 mol) was added to 100 ml of trifluoroacetic acid, and the mixture was cooled to the internal temperature of 0° C. The mixture was added dropwise with a solution obtained by dissolving 10.2 g of sodium nitrite (0.15 mol) in 100 ml of water while the temperature of the reaction mixture was kept below 5° C. After the dropwise addition was completed, the mixture was stirred at the same temperature for 15 minutes, and then the mixture was added with a solution obtained by dissolving 100 g of stannic chloride (0.54 mol) in 50 ml of concentrated hydrochloric acid while the temperature of the reaction mixture was kept below 10° C. After the completion of the dropwise addition, the crystals precipitated by addition of 250 ml of water were collected by filtration and washed with 200 ml of methylene chloride. The resulting Intermediate 14 was dried and used for the synthesis of Intermediate 15 without purification.
- The above-obtained Intermediate 14 (whole amount) and 12.9 g of 3-methyl-2-butanone (0.15 mol) were added to 140 ml of acetic acid, and the mixture was heated under stirring for 2 hours and 30 minutes. After the mixture was cooled to room temperature, the crystals precipitated were removed by filtration, and the filtrate was concentrated under reduced pressure to one quarter volume. The residue was added with 300 ml of water and 300 ml of ethyl acetate, and insoluble precipitates were removed by filtration using celite. The filtrate was extracted with ethyl acetate (300 ml, 200 ml×2), and the extract was washed with a saturated sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: hexane:ethyl acetate=3:1 to 2:1). The crystal obtained was recrystallized from 50 ml of hexane to obtain Intermediate 15. 1.3 g (yield: 4%)
- Compound 35 was synthesized from Intermediate 15 in a similar method to that for Intermediate 13 and Compound 33 (65 mg).
- MS (FAB-, Glycerin) m/z=842,804
- 1H-NMR (D2O) δ (ppm) 1.70 (s, 12H), 1.90-2.00 (m, 8H), 2.90 (t, 4H, J=7.2 Hz), 4.10 (t, 4H, J=7.2 Hz), 6.22 (d, 2H, J=14.5 Hz), 6.55 (dd, 2H, 14.5, 14.5 Hz), 7.30-7.60 (m, 17H), 7.77 (dd, 2H, J=14.5, 14.5 Hz)
- Tumor tissue pieces of mouse colon carcinoma (colon 26 carcinoma) were subcutaneously grafted to the left breast of BALB/c nude mice (5 weeks old, Clea Japan, Inc.). Ten days later when the tumor grew to a diameter of about 8 mm, the mice were subjected to the test. As a fluorescence excitation light source, a titanium sapphire laser was used. The test mice were uniformly exposed to the laser light using a ring type light guide (Sumita Optical Glass Co.) wherein dispersion of irradiation was within 10%. The irradiation power output was adjusted so that the power was about 40 μW/cm2 near skin surface of the mice. The fluorescence was excited at the maximum excitation wavelength of each compound and fluorescence emission from the mice was detected and photographed through a short wavelength cutoff filter (IR84, IR8, IR88, Fuji Photo Film CO., LTD.) with CCD camera (C4880, Hamamatsu Photonics K.K). The cutoff filter was selected to fit the excitation wavelength of the compound. The exposure time was adjusted depending on the fluorescence intensity of each compound.
Compound 2 as a test compound (0.5 mg/ml) was dissolved in physiological saline or phosphate buffer (pH7.4) and administered to the mice via a tail vein at the dose of 5.0 mg/Kg. At a given time after the administration of the test compound, the mice were anesthetized with diethyl ether and fluorescent light images of the entire body of the mice was photographed. For comparison, each of ICG (5 mg/kg, i.v.) and the following compound (Compound A) was administered and imaging was carried out in the same manner as above. The results are shown inFIGS. 1 to 3 . -
Compound 2 gave clear images of tumors at a shorter time after the administration as compared to the reference compounds. The position of tumor was not clear within 1 hour after the administration of the reference compounds. Whilst,Compound 2 successfully gave clear images of the tumor at 10 to 30 minutes after the administration and revealed to be highly effective as a fluorescent contrast agent (FIG. 1 ). - Tumor bearing mice were prepared in the same manner as Test Example 1, and conditions for irradiation was the same as those explained in Test Example 1. Compound 5, Compound 7, and
Compound 10 were used as test compounds. Each of the test compounds (0.5 mg/ml) was dissolved in physiological saline or phosphate buffer (pH 7.4) and administered to the mice via a tail vein at the dose of 5.0 mg/Kg. For comparison, the following compound (Compound B, 5 mg/kg, i.v.) was administered to the mice. - Light was generated using a tunable, pulsed, solid state laser system consisting of an optical parametric oscillator (OPO) pumped by the third harmonic of a Nd:Yag laser (Coherent Inc.). An excitation wavelength of λ ex=740 nm was chosen and guided with an optical fiber to the tumor bearing nude mice. The dye-specific fluorescence exitance was imaged using a filter combination (Corion) and an intensified CCD camera (Roper Scientific.) at different times after dye administration (
FIG. 4 ). Fluorescence imagings were taken before administration, and min, 10min 30 min, 60 min, 2 hours, 4 hours, 24 hours after intravenous dye administration via the lateral tail venous at a standard dose of 5 mg/kg. In the first 60 min, the body temperature of the animals was kept at 38° C. with heating pad. Fluorescence imaging properties of the compounds were compared in nude mice tumor models. The results are shown inFIGS. 5 to 8 . Compound 5, Compound 7, andCompound 10 gave clear images of tumors at a shorter time after the administration as compared to the reference compound (Compound B). The position of tumor was not clear within 1 hour after the administration of the reference compound (FIG. 8 ). Whilst, the compounds of the present invention successfully gave clear images of the tumor at 10 to 30 minutes after the administration (FIGS. 5 to 7 ) and revealed to be highly effective as a fluorescent contrast agent - The near infrared fluorescence contrast agent of the present invention can emit near infrared fluorescence by an excitation light. The near infrared fluorescence is superior in permeability through biological tissues, and therefore, the agent enables the detection of a lesion in a deep part of a living body.
Claims (16)
1-11. (canceled)
12. A near infrared fluorescent contrast agent comprising a pharmaceutically acceptable injectable carrier for diagnostic imaging and a compound of the following formula or a pharmaceutically acceptable salt thereof:
wherein
R1, R2, R7, and R8 independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted aryl group; or
R1 and R2 and/or R7 and R8 bind to each other to form a ring;
R3, R4, R5, R6, R9, R10, R11 and R12 independently represent a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a halogen atom, cyano group, carboxyl group, or sulfo group; or two of R3, R4, R5, R6, R9, R10, R11 and R12 bind to each other to form a ring;
X2 represents a substituted or unsubstituted C1-C15 alkyl group or a substituted or unsubstituted aryl group;
X1 is a group represented by the following formula
wherein
X1 and X2 in total have 2 or 4 carboxyl groups;
Y1 and Y2 independently represent a substituted or unsubstituted divalent linking group;
m1 represents 0 or 1;
m2 represents or 1;
m3 represents 0 or 1;
L1, L2, L3, L4, L5, L6, and L7 independently represent a substituted or unsubstituted methine group, provided that when two or more of the methine groups have substituents, the substituents bind to each other to form a ring;
M represents a hydrogen atom, a metal, or a quaternary ammonium salt; and
n represents an integer of 1 to 7 necessary for neutralizing charge.
13. The near infrared fluorescent contrast agent according to claim 12 , wherein each of m1, m2, and m3 is 1.
15. The near infrared fluorescent contrast agent according to claim 12 , wherein at least one of R3, R4, R5, R6, R9, R10, R11, and R12 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.
16. The near infrared fluorescent contrast agent according to claim 12 , wherein
Y1 represents —(CH2)pCONH—,
p represents an integer of 1 to 4, and
Y2 represents —(CH2)— or (CH2)2—.
17. The near infrared fluorescent contrast agent according to claim 12 , wherein the pharmaceutically acceptable injectable carrier for diagnostic imaging is injectable distilled water.
18. The near infrared fluorescent contrast agent according to claim 12 , wherein the pharmaceutically acceptable injectable carrier for diagnostic imaging is physiological saline.
19. The near infrared fluorescent contrast agent according to claim 12 , wherein the pharmaceutically acceptable injectable carrier for diagnostic imaging is Ringer's solution.
20. The near infrared fluorescent contrast agent according to claim 12 , wherein at least one of R3, R4, R5, R6, R9, R10, R11, and R12 is a substituted or unsubstituted aryl group.
21. The near infrared fluorescent contrast agent according to claim 12 , wherein at least one of R3, R4, R5, R6, R9, R10, R11, and R12 is a substituted or unsubstituted heteroaryl group.
22. The near infrared fluorescent contrast agent according to claim 12 , wherein Y1 represents —(CH2)pCONH—.
23. The near infrared fluorescent contrast agent according to claim 12 , wherein p represents an integer of 1 to 4.
24. The near infrared fluorescent contrast agent according to claim 12 , wherein Y2 represents —(CH2)— or (CH2)2—.
25. The near infrared fluorescent contrast agent according to claim 14 , wherein each of m1, m2, and m3 is 1.
26. The near infrared fluorescent contrast agent according to claim 16 , wherein each of m1, m2, and m3 is 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/147,717 US20090041670A1 (en) | 2002-03-07 | 2008-06-27 | Near Infrared Fluorescent Contrast Agent And Method For Fluorescence Imaging |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002109794A JP2003261464A (en) | 2002-03-07 | 2002-03-07 | Near infrared fluorescent contrast agent and fluorescent contrast radiography |
JP109794/2002 | 2002-03-07 | ||
US10/506,819 US7473415B2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
PCT/EP2003/002358 WO2003074091A2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
US12/147,717 US20090041670A1 (en) | 2002-03-07 | 2008-06-27 | Near Infrared Fluorescent Contrast Agent And Method For Fluorescence Imaging |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/002358 Division WO2003074091A2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
US10/506,819 Division US7473415B2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090041670A1 true US20090041670A1 (en) | 2009-02-12 |
Family
ID=27785574
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/506,819 Expired - Fee Related US7473415B2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
US12/147,717 Abandoned US20090041670A1 (en) | 2002-03-07 | 2008-06-27 | Near Infrared Fluorescent Contrast Agent And Method For Fluorescence Imaging |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/506,819 Expired - Fee Related US7473415B2 (en) | 2002-03-07 | 2003-03-07 | Near infrared fluorescent contrast agent and method for fluorescence imaging |
Country Status (20)
Country | Link |
---|---|
US (2) | US7473415B2 (en) |
EP (1) | EP1480683B1 (en) |
JP (2) | JP2003261464A (en) |
KR (1) | KR20040099301A (en) |
CN (1) | CN100340298C (en) |
AT (1) | ATE395088T1 (en) |
AU (1) | AU2003208700B2 (en) |
BR (1) | BR0308217A (en) |
CA (1) | CA2478272A1 (en) |
DE (1) | DE60320952D1 (en) |
DK (1) | DK1480683T3 (en) |
ES (1) | ES2305444T3 (en) |
HK (1) | HK1079110A1 (en) |
MX (1) | MXPA04008664A (en) |
NO (1) | NO20044244L (en) |
PL (1) | PL370918A1 (en) |
PT (1) | PT1480683E (en) |
RU (1) | RU2350355C9 (en) |
WO (1) | WO2003074091A2 (en) |
ZA (1) | ZA200408072B (en) |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4445065A1 (en) * | 1994-12-07 | 1996-06-13 | Diagnostikforschung Inst | Methods for in-vivo diagnostics using NIR radiation |
JP2003261464A (en) * | 2002-03-07 | 2003-09-16 | Fuji Photo Film Co Ltd | Near infrared fluorescent contrast agent and fluorescent contrast radiography |
US7682602B2 (en) * | 2003-12-19 | 2010-03-23 | Konica Minolta Medical & Graphic, Inc. | Near-infrared fluorescent contrast medium |
US7233392B2 (en) * | 2004-03-25 | 2007-06-19 | Opotek, Inc. | Spectral imaging device with tunable light source |
US7910753B2 (en) * | 2004-09-10 | 2011-03-22 | Anaspec Incorporated | Cyanine dyes and their applications as luminescence quenching compounds |
US8227621B2 (en) | 2005-06-30 | 2012-07-24 | Li-Cor, Inc. | Cyanine dyes and methods of use |
WO2009012109A2 (en) * | 2007-07-13 | 2009-01-22 | Emory University | Cyanine-containing compounds for cancer imaging and treatment |
GB0718957D0 (en) * | 2007-09-28 | 2007-11-07 | Ge Healthcare Ltd | Optical imaging agents |
US20090214436A1 (en) * | 2008-02-18 | 2009-08-27 | Washington University | Dichromic fluorescent compounds |
US20090240143A1 (en) * | 2008-03-12 | 2009-09-24 | Mauna Kea Technologies | Method and an optical probe for in vivo imaging of a mucosa in a biliary or pancreatic system and a method for selectively operating a tissue sampling of a mucosa in a biliary or pancreatic system |
EP2303337A4 (en) * | 2008-06-13 | 2014-09-03 | Cedars Sinai Medical Center | Small molecule ligand-drug conjugates for targeted cancer therapy |
AU2010236189B2 (en) * | 2009-04-17 | 2015-01-29 | Li-Cor, Inc. | Fluorescent imaging with substituted cyanine dyes |
CN101574529B (en) * | 2009-06-04 | 2011-04-20 | 中国人民解放军第三军医大学 | Application of near infrared fluorescent chemical in lymphaden imaging and angiogram |
JP2011046663A (en) | 2009-08-28 | 2011-03-10 | Fujifilm Corp | Near infrared fluorescent imaging agent |
JP2011046662A (en) * | 2009-08-28 | 2011-03-10 | Fujifilm Corp | Near infrared fluorescent imaging agent |
US8401618B2 (en) | 2009-08-28 | 2013-03-19 | Visen Medical, Inc. | Systems and methods for tomographic imaging in diffuse media using a hybrid inversion technique |
EP2480126B1 (en) | 2009-09-22 | 2017-01-04 | VisEn Medical, Inc. | Systems and methods for virtual index-matching of diffusive media |
JP5462596B2 (en) * | 2009-11-12 | 2014-04-02 | 富士フイルム株式会社 | Fluorescence imaging device |
US8273875B2 (en) | 2009-11-16 | 2012-09-25 | University Of Notre Dame Du Lac | High performance luminescent compounds |
WO2012054749A1 (en) | 2010-10-20 | 2012-04-26 | Li-Cor, Inc. | Cyanine dyes and their conjugates |
EP2599428B1 (en) | 2011-03-15 | 2017-09-06 | Olympus Corporation | Medical apparatus |
EP2599429B1 (en) * | 2011-03-15 | 2015-11-18 | Olympus Corporation | Medical apparatus |
EP3553075A1 (en) | 2012-01-23 | 2019-10-16 | Washington University | Goggle imaging systems and methods |
WO2014062716A1 (en) | 2012-10-15 | 2014-04-24 | Visen Medical, Inc. | Systems, methods, and apparatus for imaging of diffuse media featuring cross-modality weighting of fluorescent and bioluminescent sources |
CN106455979A (en) | 2013-12-31 | 2017-02-22 | 纪念斯隆-凯特琳癌症中心 | Systems, methods, and apparatus for multichannel imaging of fluorescent sources in real time |
RU2017122621A (en) | 2014-12-15 | 2019-01-17 | Мемориал Слоун Кеттеринг Кэнсер Сентр | CYCLIC PEPTIDES WITH IMPROVED NERVE BINDING SELECTIVITY, NANOPARTICLES RELATED TO THE INDICATED CYCLIC PEPTIDES, AND THEIR APPLICATION FOR IMAGING NERVOUS TIME NEMAL TISSUE IN VIVO |
KR20160086481A (en) * | 2015-01-09 | 2016-07-20 | 차의과학대학교 산학협력단 | A novel organic compound and a near infrared fluoroscent contrast agent comprising thereof, and nanoparticulation method of the contrast agent |
WO2016179350A1 (en) | 2015-05-06 | 2016-11-10 | Washington University | Compounds having rd targeting motifs and methods of use thereof |
WO2017106525A1 (en) | 2015-12-15 | 2017-06-22 | Memorial Sloan Kettering Cancer Center | Imaging systems and methods for tissue differentiation, e.g., for intraoperative visualization |
JP6752582B2 (en) * | 2016-02-08 | 2020-09-09 | キヤノン株式会社 | Contrast agent for photoacoustic imaging |
JP2020500863A (en) | 2016-11-30 | 2020-01-16 | メモリアル スローン ケタリング キャンサー センター | Inhibitor-functionalized ultra-small nanoparticles and methods thereof |
WO2018119204A1 (en) * | 2016-12-21 | 2018-06-28 | Profusa, Inc. | Polymerizable near-ir dyes |
WO2019190549A1 (en) | 2018-03-30 | 2019-10-03 | Perkinelmer Health Sciences, Inc. | Systems and methods for 3d reconstruction of anatomical organs and inclusions using short-wave infrared (swir) projection tomography |
CN109824871B (en) * | 2019-01-08 | 2021-04-16 | 南京邮电大学 | Near-infrared two-zone fluorescent quinoid polymer, preparation method and application thereof |
WO2021119423A1 (en) | 2019-12-13 | 2021-06-17 | Washington University | Near infrared fluorescent dyes, formulations and related methods |
EP4015004A1 (en) | 2020-12-18 | 2022-06-22 | Phi Pharma SA | Proteoglycan specific branched peptides |
WO2023210645A1 (en) * | 2022-04-27 | 2023-11-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Icg lipid derivative, and lipid microparticles each containing same |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7473415B2 (en) * | 2002-03-07 | 2009-01-06 | Fuji Photo Film Co., Ltd. | Near infrared fluorescent contrast agent and method for fluorescence imaging |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19539409C2 (en) * | 1995-10-11 | 1999-02-18 | Diagnostikforschung Inst | Contrast agent for near infrared diagnostics |
DE19957007A1 (en) * | 1999-11-26 | 2001-05-31 | Few Chemicals Gmbh Wolfen | New cyanine dyes, used as fluorescent marking dyes, e.g. for analysis of clinical, biological, biochemical or chemical substance, have sulfoaryl and N-sulfoalkyl groups, meso-halo-methine chain and reactive binding group |
US6395257B1 (en) * | 2000-01-18 | 2002-05-28 | Mallinckrodt Inc. | Dendrimer precursor dyes for imaging |
JP2001288197A (en) * | 2000-04-10 | 2001-10-16 | Fuji Photo Film Co Ltd | Fluorescent nucleotide |
US6939975B2 (en) * | 2000-08-08 | 2005-09-06 | Fuji Photo Film Co., Ltd. | Cyanine dyes |
US6663847B1 (en) * | 2000-10-13 | 2003-12-16 | Mallinckrodt Inc. | Dynamic organ function monitoring agents |
-
2002
- 2002-03-07 JP JP2002109794A patent/JP2003261464A/en active Pending
-
2003
- 2003-03-07 AU AU2003208700A patent/AU2003208700B2/en not_active Ceased
- 2003-03-07 DE DE60320952T patent/DE60320952D1/en not_active Expired - Fee Related
- 2003-03-07 PL PL03370918A patent/PL370918A1/en not_active Application Discontinuation
- 2003-03-07 CN CNB038054604A patent/CN100340298C/en not_active Expired - Fee Related
- 2003-03-07 DK DK03706606T patent/DK1480683T3/en active
- 2003-03-07 US US10/506,819 patent/US7473415B2/en not_active Expired - Fee Related
- 2003-03-07 WO PCT/EP2003/002358 patent/WO2003074091A2/en active IP Right Grant
- 2003-03-07 ES ES03706606T patent/ES2305444T3/en not_active Expired - Lifetime
- 2003-03-07 AT AT03706606T patent/ATE395088T1/en not_active IP Right Cessation
- 2003-03-07 CA CA002478272A patent/CA2478272A1/en not_active Abandoned
- 2003-03-07 PT PT03706606T patent/PT1480683E/en unknown
- 2003-03-07 RU RU2004129766/15A patent/RU2350355C9/en not_active IP Right Cessation
- 2003-03-07 JP JP2003579524A patent/JP2005519977A/en active Pending
- 2003-03-07 BR BR0308217-2A patent/BR0308217A/en not_active IP Right Cessation
- 2003-03-07 MX MXPA04008664A patent/MXPA04008664A/en active IP Right Grant
- 2003-03-07 EP EP03706606A patent/EP1480683B1/en not_active Expired - Lifetime
- 2003-03-07 KR KR10-2004-7013937A patent/KR20040099301A/en not_active Application Discontinuation
-
2004
- 2004-10-06 ZA ZA200408072A patent/ZA200408072B/en unknown
- 2004-10-06 NO NO20044244A patent/NO20044244L/en not_active Application Discontinuation
-
2005
- 2005-12-08 HK HK05111271A patent/HK1079110A1/en not_active IP Right Cessation
-
2008
- 2008-06-27 US US12/147,717 patent/US20090041670A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7473415B2 (en) * | 2002-03-07 | 2009-01-06 | Fuji Photo Film Co., Ltd. | Near infrared fluorescent contrast agent and method for fluorescence imaging |
Also Published As
Publication number | Publication date |
---|---|
HK1079110A1 (en) | 2006-03-31 |
JP2003261464A (en) | 2003-09-16 |
MXPA04008664A (en) | 2004-12-06 |
EP1480683A2 (en) | 2004-12-01 |
RU2004129766A (en) | 2005-08-10 |
RU2350355C2 (en) | 2009-03-27 |
NO20044244L (en) | 2004-12-06 |
WO2003074091A3 (en) | 2004-03-11 |
CN1638810A (en) | 2005-07-13 |
AU2003208700A1 (en) | 2003-09-16 |
DE60320952D1 (en) | 2008-06-26 |
BR0308217A (en) | 2004-12-21 |
PL370918A1 (en) | 2005-06-13 |
JP2005519977A (en) | 2005-07-07 |
US7473415B2 (en) | 2009-01-06 |
EP1480683B1 (en) | 2008-05-14 |
PT1480683E (en) | 2008-07-24 |
ES2305444T3 (en) | 2008-11-01 |
CN100340298C (en) | 2007-10-03 |
US20050226815A1 (en) | 2005-10-13 |
WO2003074091A2 (en) | 2003-09-12 |
CA2478272A1 (en) | 2003-09-12 |
KR20040099301A (en) | 2004-11-26 |
ZA200408072B (en) | 2006-06-28 |
AU2003208700B2 (en) | 2007-12-20 |
DK1480683T3 (en) | 2008-08-18 |
RU2350355C9 (en) | 2009-05-27 |
ATE395088T1 (en) | 2008-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7473415B2 (en) | Near infrared fluorescent contrast agent and method for fluorescence imaging | |
KR100531708B1 (en) | Near Infrared Fluorescent Contrast Agent and Fluorescence Imaging | |
US7252815B2 (en) | Pathological tissue detection and treatment employing targeted benzoindole optical agents | |
CA2394539C (en) | Near infrared fluorescent contrast agent and fluorescence imaging | |
EP1443860A2 (en) | Carbocyanine dyes for tandem, photodiagnostic and therapeutic applications | |
EP1471822A1 (en) | DYE&minus;BIOCONJUGATES FOR SIMULTANEOUS OPTICAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS | |
EP2201897A2 (en) | Tumor targeted photodiagnostic-phototherapeutic agents | |
JP3507060B2 (en) | Near-infrared fluorescent contrast agent and fluorescence imaging |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT, GERMAN D Free format text: CHANGE OF NAME;ASSIGNOR:SCHERING AKTIENGESELLSCHAFT;REEL/FRAME:023010/0195 Effective date: 20061229 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |