JP2023106756A - Boronophenylalanine amide derivative - Google Patents
Boronophenylalanine amide derivative Download PDFInfo
- Publication number
- JP2023106756A JP2023106756A JP2022007678A JP2022007678A JP2023106756A JP 2023106756 A JP2023106756 A JP 2023106756A JP 2022007678 A JP2022007678 A JP 2022007678A JP 2022007678 A JP2022007678 A JP 2022007678A JP 2023106756 A JP2023106756 A JP 2023106756A
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- JP
- Japan
- Prior art keywords
- substituted
- unsubstituted
- arh
- amino
- alkyl
- 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.)
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- ITNWMTPJKMYIQC-QMMMGPOBSA-N B(O)(O)N[C@@H](CC1=CC=CC=C1)C(=O)N Chemical class B(O)(O)N[C@@H](CC1=CC=CC=C1)C(=O)N ITNWMTPJKMYIQC-QMMMGPOBSA-N 0.000 title abstract description 25
- -1 boronic acid ester Chemical class 0.000 claims abstract description 169
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 229910052796 boron Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical class 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- OXCIGGOKELWQSU-UHFFFAOYSA-N NBO Chemical compound NBO OXCIGGOKELWQSU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004740 (C1-C6) haloalkylsulfanyl group Chemical group 0.000 claims description 4
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 229940039227 diagnostic agent Drugs 0.000 claims description 3
- 239000000032 diagnostic agent Substances 0.000 claims description 3
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000002285 radioactive effect Effects 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 67
- 210000004027 cell Anatomy 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 18
- 102100038204 Large neutral amino acids transporter small subunit 1 Human genes 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 108091006232 SLC7A5 Proteins 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZOXJGFHDIHLPTG-BJUDXGSMSA-N Boron-10 Chemical compound [10B] ZOXJGFHDIHLPTG-BJUDXGSMSA-N 0.000 description 6
- 102100038235 Large neutral amino acids transporter small subunit 2 Human genes 0.000 description 6
- 108091006238 SLC7A8 Proteins 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 6
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical class OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 150000001639 boron compounds Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000004210 ether based solvent Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000002603 single-photon emission computed tomography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- IKTJTGWJQSDQDK-UHFFFAOYSA-N (4-chlorophenyl)methanimine Chemical compound ClC1=CC=C(C=N)C=C1 IKTJTGWJQSDQDK-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- KYIYLQNLZYNVQY-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(Br)=CC=C1CBr KYIYLQNLZYNVQY-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000605020 Homo sapiens Large neutral amino acids transporter small subunit 1 Proteins 0.000 description 2
- 101000996834 Homo sapiens Linker for activation of T-cells family member 2 Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 238000004380 ashing Methods 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
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Abstract
Description
本発明は、ボロノフェニルアラニンアミド誘導体に関する。 The present invention relates to boronophenylalanine amide derivatives.
癌の治療方法として、ホウ素中性子捕捉療法(BNCT)がある。ホウ素中性子捕捉療法は、ホウ素10同位体(10B)を含むホウ素化合物を癌細胞に取り込ませ、低エネルギーの中性子線(例えば熱中性子)を照射して、細胞内で起こる核反応により局所的に癌細胞を破壊する治療方法である。この治療方法では、10Bを含むホウ素化合物を癌組織の細胞に選択的に蓄積させることが、治療効果を高める上で重要であるため、癌細胞に選択的に取り込まれるホウ素化合物を開発することが必要となる。 Boron neutron capture therapy (BNCT) is a cancer treatment method. Boron neutron capture therapy involves taking a boron compound containing boron 10 isotope ( 10 B) into cancer cells, irradiating low-energy neutron beams (e.g. thermal neutrons), and localizing nuclear reactions occurring within the cells. It is a treatment method that destroys cancer cells. In this therapeutic method, it is important to selectively accumulate boron compounds containing 10 B in cancer tissue cells in order to enhance the therapeutic effect. Is required.
BNCTに用いる薬剤として基本骨格にホウ素原子又はホウ素原子団を導入した4-ボロノ-フェニルアラニンの誘導体が合成されている。実際の臨床で用いられている薬剤としては、4-ボロノ-フェニルアラニンの誘導体(L-BPA)やメルカプトウンデカハイドロドデカボレート(BSH)がある。4-ボロノ-フェニルアラニンは、フェニルアラニンのミミックとしてアミノ酸トランスポーターの一種であるLAT1(L-type Amino acid Transporter 1)に取り込まれる。癌細胞ではLAT1の発現が亢進しているため、L-BPAが蓄積しやすく、その性質を利用して癌の治療に利用されている(例えば、非特許文献1参照)。 Derivatives of 4-borono-phenylalanine having a boron atom or a boron atomic group introduced into the basic skeleton have been synthesized as drugs for use in BNCT. Drugs used clinically include 4-borono-phenylalanine derivative (L-BPA) and mercaptoundecahydrododecaborate (BSH). 4-borono-phenylalanine is incorporated into LAT1 (L-type Amino acid Transporter 1), a kind of amino acid transporter, as a mimic of phenylalanine. Since LAT1 expression is enhanced in cancer cells, L-BPA is likely to accumulate, and this property is utilized in the treatment of cancer (see, for example, Non-Patent Document 1).
しかしながら、腫瘍細胞の種類や悪性度によっては、LAT1が亢進していない場合がある。4-ボロノ-フェニルアラニンは、LAT1経由で取り込まれるため、LAT1が亢進していない部位に蓄積されず、このような場合には、BNCTの適用ができない。 However, depending on the type and degree of malignancy of tumor cells, LAT1 may not be elevated. Since 4-borono-phenylalanine is taken up via LAT1, it is not accumulated in sites where LAT1 is not enhanced, and BNCT cannot be applied in such cases.
従って、LAT1経由で取り込まれなくても、腫瘍細胞に取り込まれる可能性のある新たな化合物群の創製が求められている。 Therefore, it is desired to create a new group of compounds that may be taken up by tumor cells even if they are not taken up via LAT1.
本発明は、ボロノフェニルアラニンアミド誘導体を提供することを目的とする。 An object of the present invention is to provide boronophenylalanine amide derivatives.
本発明者らは前記課題を解決すべく鋭意検討を重ねた結果、新たなボロノフェニルアラニンアミド誘導体を見出し、本発明を完成するに至った。 The present inventors have made intensive studies to solve the above problems, and as a result, have found a new boronophenylalanine amide derivative and completed the present invention.
すなわち、本発明は、下記化合物を提供する。
[1]
下記式(I)で表される化合物又はその薬学的に許容される塩:
R1、R2は、B原子と共に、ボロン酸(‐B(OH)2)、ボロン酸エステル、又はボロン酸アミドの置換基を表し;
R3は、H、ハロゲン、ヒドロキシ、シアノ、アミノ、C1-C6アルキルアミノ、C1-C6アルキル、C1-C6アルコキシ、ベンジルオキシ、C1-C6アルコキシC1-C6アルキル、ニトロ、C1-C6ハロアルキル、カルバモイル、C1-C6アルキルアミノカルボニル、C1-C6アルコキシカルボニル、C1-C6アルキルカルボニル、COOR10(R10は、H又はC1-C6アルキル、アミノ、C1-C6アルキルアミノ)、C1-C6ハロアルキルスルファニル、C1-C6ハロアルキルスルフィニル、C1-C6ハロアルキルスルホニル、C1-C6アルキルチオ、C1-C6アルキルスルフィニル、C1-C6アルキルスルホニル、アミノスルホニル、スルホ、及びスルファモイルからなる群から、独立して選択される基を表し;
sは、1~4のいずれかの整数を表し;
R4は、H、C1-C6アルキル、ベンジル、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表し;
R5は、H、置換もしくは非置換のC1-C6アルキル、置換もしくは非置換のC2-6アルケニル、置換もしくは非置換のC2-6アルキニル、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、置換もしくは非置換のC1-C6アルコキシ、置換もしくは非置換のC1-C6アルコキシC1-C6アルキル、置換もしくは非置換のアシル、置換もしくは非置換のスルホニル、置換もしくは非置換のカルバモイル、C1-C6アルコキシカルボニル、置換もしくは非置換のC3-C7シクロアルキル、置換もしくは非置換のC3-C7シクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表すか、又は、R4R5がNと共に、C3-C7ヘテロシクロアルキルを形成し;
R6はH又は置換されていてもよいC1-C6アルキル、又は隣接するメチレン部とベンゼン環に縮合する形の環構造を形成してもよいことを表し、ここで、環構造は、非置換のC5-7シクロアルキル又は非置換のC5-7シクロアルケニルを表す。
[2]
前記R3は、独立して、H、Cl、F、C1-C3アルキル、C1-C3アルコキシ、C1-C6アルキルチオ、CH2X、CHX2、又はCX3(XはFを表わす)を表す、[1]に記載の化合物又はその薬学的に許容される塩。
[3]
前記R4は、H又はC1-C6アルキルを表し;
前記R5は、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表す、[1]又は[2]に記載の化合物又はその薬学的に許容される塩。
[4]
前記R4は、H又はC1-C6アルキルを表し;
前記R5は、アリール置換C1-C6アルキルを表す、[1]又は[2]に記載の化合物又はその薬学的に許容される塩。
[5]
前記R4R5がNと共に、C3-C7ヘテロシクロアルキルを形成する、[1]又は[2]に記載の化合物又はその薬学的に許容される塩。
[6]
[1]~[5]のいずれか1項に記載の化合物又はその薬学的に許容される塩を含む、BNCT用薬剤。
[7]
[1]~[5]のいずれか1項に記載の化合物又はその薬学的に許容される塩のR3のいずれか1つの部位、R4、又はR5のいずれかに放射性同位体を置換基として含有する診断薬。
Specifically, the present invention provides the following compounds.
[1]
A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
R 1 , R 2 together with the B atom represent substituents of boronic acid (-B(OH) 2 ), boronic ester, or boronic acid amide;
R 3 is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR 10 (R 10 is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R 4 represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R 4 R 5 together with N form C3-C7 heterocycloalkyl;
R 6 represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-7 cycloalkyl or unsubstituted C5-7 cycloalkenyl.
[2]
said R 3 independently represents H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH 2 X, CHX 2 , or CX 3 (X represents F); The compound of [1] or a pharmaceutically acceptable salt thereof.
[3]
said R 4 represents H or C1-C6 alkyl;
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R 5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[4]
said R 4 represents H or C1-C6 alkyl;
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said R 5 represents an aryl-substituted C1-C6 alkyl.
[5]
The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said R 4 R 5 together with N form C3-C7 heterocycloalkyl.
[6]
A BNCT agent comprising the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof.
[7]
Substitution of a radioactive isotope at any one site of R 3 , R 4 or R 5 of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof A diagnostic agent containing as a group.
本発明の新規な化合物は、単独又は他の化合物と併用することで、BNCTの更なる適用拡大に有用であり得る。 The novel compounds of the present invention may be useful for further expanding the application of BNCT, either alone or in combination with other compounds.
本明細書において、不斉炭素を持つ化合物を表す場合には、特に示さない限り、当該化合物は、ラセミ体、R体、S体のいずれでも良いものとする。 In the present specification, when a compound having an asymmetric carbon is indicated, the compound may be racemic, R-isomer, or S-isomer unless otherwise specified.
[ボロノフェニルアラニンアミド誘導体〕
本発明のボロノフェニルアラニンアミド誘導体は、下記式(I)で表される化合物又はその薬学的に許容される塩である。
ここで、式(I)中、
R1、R2は、B原子と共に、ボロン酸(‐B(OH)2)、ボロン酸エステル、又はボロン酸アミドの置換基を表し;
R3は、H、ハロゲン、ヒドロキシ、シアノ、アミノ、C1-C6アルキルアミノ、C1-C6アルキル、C1-C6アルコキシ、ベンジルオキシ、C1-C6アルコキシC1-C6アルキル、ニトロ、C1-C6ハロアルキル、カルバモイル、C1-C6アルキルアミノカルボニル、C1-C6アルコキシカルボニル、C1-C6アルキルカルボニル、COOR10(R10は、H又はC1-C6アルキル、アミノ、C1-C6アルキルアミノ)、C1-C6ハロアルキルスルファニル、C1-C6ハロアルキルスルフィニル、C1-C6ハロアルキルスルホニル、C1-C6アルキルチオ、C1-C6アルキルスルフィニル、C1-C6アルキルスルホニル、アミノスルホニル、スルホ、及びスルファモイルからなる群から、独立して選択される基を表し;
sは、1~4のいずれかの整数を表し;
R4は、H、C1-C6アルキル、ベンジル、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表し;
R5は、H、置換もしくは非置換のC1-C6アルキル、置換もしくは非置換のC2-6アルケニル、置換もしくは非置換のC2-6アルキニル、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、置換もしくは非置換のC1-C6アルコキシ、置換もしくは非置換のC1-C6アルコキシC1-C6アルキル、置換もしくは非置換のアシル、置換もしくは非置換のスルホニル、置換もしくは非置換のカルバモイル、C1-C6アルコキシカルボニル、置換もしくは非置換のC3-C7シクロアルキル、置換もしくは非置換のC3-C7シクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表すか、又は、R4R5がNと共に、C3-C7ヘテロシクロアルキルを形成し;
R6はH又は置換されていてもよいC1-C6アルキル、又は隣接するメチレン部とベンゼン環に縮合する形の環構造を形成してもよいことを表し、ここで、環構造は、非置換のC5-C7シクロアルキル又は非置換のC5-7シクロアルケニルを表す。
[Boronophenylalanine amide derivative]
The boronophenylalanine amide derivative of the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
Here, in formula (I),
R 1 , R 2 together with the B atom represent substituents of boronic acid (-B(OH) 2 ), boronic ester, or boronic acid amide;
R 3 is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR 10 (R 10 is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R 4 represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R 4 R 5 together with N form C3-C7 heterocycloalkyl;
R 6 represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-C7 cycloalkyl or unsubstituted C5-7 cycloalkenyl.
本明細書において、ハロゲンは、F、Cl、Br、Iのいずれでも良いが、F、Cl、Brであることが特に好ましい。 In this specification, halogen may be any of F, Cl, Br and I, but F, Cl and Br are particularly preferred.
本明細書において、C1-C6のアルキルとは、直鎖状又は分岐状のC1-C6の飽和炭化水素基をいう。C1-C6アルキル基の例としては、メチル、エチル、プロピル(例えば、n-プロピル及びイソプロピル)、ブチル(例えば、n-ブチル、イソブチル、t-ブチル)、ペンチル(例えば、n-ペンチル、イソペンチル、ネオペンチル)等が含まれる。好ましくは、直鎖状又は分岐状のC1-C4のアルキル基であり、限定はされないが、例えば、メチル基、エチル基、イソプロピル基、ブチル基等が挙げられる。 In the present specification, C1-C6 alkyl refers to a linear or branched C1-C6 saturated hydrocarbon group. Examples of C1-C6 alkyl groups are methyl, ethyl, propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, t-butyl), pentyl (eg n-pentyl, isopentyl, neopentyl), etc. Preferred are linear or branched C1-C4 alkyl groups, including, but not limited to, methyl, ethyl, isopropyl and butyl groups.
本明細書において、C2-C6のアルケニルとは、直鎖状又は分岐状のC2-C6の不飽和炭化水素基のうち、二重結合を含む基をいう。C2-C6アルケニル基の例としては、エテニル、プロぺニル、ブテニル等が挙げられる。 In the present specification, C2-C6 alkenyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a double bond. Examples of C2-C6 alkenyl groups include ethenyl, propenyl, butenyl, and the like.
本明細書において、C2-C6アルキニルとは、直鎖状又は分岐状のC2-C6の不飽和炭化水素基のうち、三重結合を含む基をいう。C2-C6アルキニル基の例としては、アセチレン、メチルアセチレン、ブチン、ペンチン等が挙げられる。 In the present specification, C2-C6 alkynyl refers to a linear or branched C2-C6 unsaturated hydrocarbon group containing a triple bond. Examples of C2-C6 alkynyl groups include acetylene, methylacetylene, butyne, pentyne, and the like.
本明細書において、C1-C6ハロアルキルとは、1つ以上のハロゲン置換基を有するC1-C6アルキル基を指す。C1-C6ハロアルキル基は、好ましくは、C2X5、CH2X、CHX2、又はCX3(XはCl、F、Br又はIを表わす)で表され、限定はされないが、例えば、CF3、C2F5、CHF2、CCl3、CHCl2、C2Cl5等が含まれる。 As used herein, C1-C6 haloalkyl refers to a C1-C6 alkyl group having one or more halogen substituents. A C1-C6 haloalkyl group is preferably represented by C 2 X 5 , CH 2 X, CHX 2 or CX 3 (where X represents Cl, F, Br or I) and is not limited to, for example CF 3 , C2F5 , CHF2 , CCl3 , CHCl2 , C2Cl5 and the like.
本明細書において、C1-C6アルコキシとは、直鎖状又は分岐状のC1-C6アルキル基と酸素分子を有する基を表す。C1-C6アルコキシは、好ましくは、直鎖状又は分岐状のC1-C4のアルキルを有し、限定はされないが、例えば、メトキシ、エトキシ、イソプロポキシ、ブトキシ等が挙げられる。 As used herein, C1-C6 alkoxy represents a group having a linear or branched C1-C6 alkyl group and an oxygen molecule. C1-C6 alkoxy preferably has linear or branched C1-C4 alkyl, including, but not limited to, methoxy, ethoxy, isopropoxy, butoxy and the like.
本明細書において、C1-C6アルコキシC1-C6アルキルとしては、限定はされないが、メトキシエチル、エトキシエチル等が挙げられる。 As used herein, C1-C6 alkoxy C1-C6 alkyl includes, but is not limited to, methoxyethyl, ethoxyethyl and the like.
本明細書において、C1-C6アルキルアミノは、NR11R12として表され、R11R12がそれぞれ、独立してH又はC1-C6アルキルを表すような基(但し、R11とR12とが共にHである場合を除く)を意味する。限定はされないが、メチルアミノ、ジメチルアミノ、エチルアミノ、i-プロピルアミノ等が挙げられる。 As used herein, C1-C6 alkylamino is represented as NR 11 R 12 , and groups such that each R 11 R 12 independently represents H or C1-C6 alkyl (with the proviso that R 11 and R 12 and are both H). Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, i-propylamino, and the like.
本明細書において、C1-C6アルキルアミノカルボニルは、CONR13R14として表され、R13、R14は、それぞれ独立して、H又はC1-C6アルキルを表すような基(但し、R13とR14とが共にHである場合を除く)を意味する。限定はされないが、メチルアミノカルボニル、ジメチルアミノカルボニル、エチルアミノカルボニル、i-プロピルアミノカルボニル等が挙げられる。 In the present specification, C1-C6 alkylaminocarbonyl is represented as CONR 13 R 14 , and R 13 and R 14 each independently represent H or a group representing C1-C6 alkyl (with the proviso that R 13 and and R 14 are both H). Examples include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, i-propylaminocarbonyl, and the like.
本明細書において、C1-C6アルキルカルボニルとしては、限定はされないが、メチルカルボニル、エチルカルボニル等が挙げられる。 As used herein, C1-C6 alkylcarbonyl includes, but is not limited to, methylcarbonyl, ethylcarbonyl, and the like.
本明細書において、C1-C6アルコキシカルボニルとしては、限定はされないが、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、sec-ブトキシカルボニル、tert-ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニル等が挙げられる。 As used herein, C1-C6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxycarbonyl and the like.
本明細書において、COOR10(R10は、H又はC1-C6アルキル、アミノ、アルキルアミノ(NR11R12(R11R12は、それぞれ独立して、H又はC1-C6アルキルを表す))としては、限定はされないが、メチルオキシカルボニル、アミノオキシカルボニル等が挙げられる。 As used herein, COOR 10 (R 10 is H or C1-C6 alkyl, amino, alkylamino (NR 11 R 12 (R 11 R 12 each independently represents H or C1-C6 alkyl)) Examples include, but are not limited to, methyloxycarbonyl, aminooxycarbonyl, and the like.
本明細書において、C1-C6ハロアルキルスルファニル、C1-C6ハロアルキルスルフィニル、C1-C6ハロアルキルスルホニルとしては、限定はされないが、トリフルオロメチルスルファニル、トリフルオロメチルスルフィニル基、又はトリフルオロメチルスルホニル等が挙げられる。 As used herein, C1-C6 haloalkylsulfanyl, C1-C6 haloalkylsulfinyl, and C1-C6 haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfanyl, trifluoromethylsulfinyl group, or trifluoromethylsulfonyl. .
本明細書において、C1-C6アルキルチオとしては、限定はされないが、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、ヘシルチオ等が挙げられる。 As used herein, C1-C6 alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hesylthio and the like.
本明細書において、C1-C6アルキルスルフィニルとしては、限定はされないが、メチルスルフィニル、エチルスルフィニル等が挙げられる。 As used herein, C1-C6 alkylsulfinyl includes, but is not limited to, methylsulfinyl, ethylsulfinyl and the like.
本明細書において、C1-C6アルキルスルホニルとしては、限定はされないが、メチルスルホニル、エチルスルホニル等が挙げられる。 As used herein, C1-C6 alkylsulfonyl includes, but is not limited to, methylsulfonyl, ethylsulfonyl and the like.
本明細書において、置換されたC1-C6アルキルとしては、限定はされないが、例えば、1か所~3カ所の水素原子が他の基で置換された直鎖又は分岐C1-C6アルキルが含まれる。 As used herein, substituted C1-C6 alkyl includes, but is not limited to, linear or branched C1-C6 alkyl in which 1 to 3 hydrogen atoms are substituted with other groups. .
本明細書において、置換されたC2-6アルケニルとしては、限定はされないが、例えば、1か所又は2カ所の水素原子が他の基で置換された直鎖又は分岐C2-6アルケニルが含まれる。 As used herein, substituted C2-6 alkenyl includes, but is not limited to, straight chain or branched C2-6 alkenyl in which one or two hydrogen atoms are substituted with other groups. .
本明細書において、置換されたC2-6アルキニルとしては、限定はされないが、1か所又は2カ所の水素原子が他の基で置換された直鎖又は分岐C2-6アルキニルが含まれる。 As used herein, substituted C2-6 alkynyl includes, but is not limited to, straight chain or branched C2-6 alkynyl in which one or two hydrogen atoms are replaced with other groups.
本明細書において、置換されたC1-C6アルコキシとしては、限定はされないが、1か所又は2カ所の水素原子が他の基で置換された直鎖又は分岐C1-C6アルコキシが含まれる。 As used herein, substituted C1-C6 alkoxy includes, but is not limited to, linear or branched C1-C6 alkoxy in which one or two hydrogen atoms are replaced with other groups.
本明細書において、置換されたC1-C6アルコキシC1-C6アルキルとしては、限定はされないが、1か所又は2カ所の水素原子が他の基で置換された直鎖又は分岐C1-C6アルコキシC1-C6アルキルが含まれる。 As used herein, substituted C1-C6 alkoxy C1-C6 alkyl includes, but is not limited to, linear or branched C1-C6 alkoxy C1 having one or two hydrogen atoms replaced with other groups. -C6 alkyl is included.
ここで、上記、置換されたC1-C6アルキル、置換されたC2-6アルケニル、置換されたC2-6アルキニル、置換されたC1-C6アルコキシ、置換されたC1-C6アルコキシC1-C6アルキル等において、水素原子の代わりに置換される基は、例えば、ハロゲン、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ルチオ(フェニルチオ等)、置換もしくは非置換のアリ一ルアミノ(フェニルアミノ等)、置換もしくは非置換のアリ一ル、置換もしくは非置換のへテロアリ一ルである。 Here, in the above substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 alkoxy C1-C6 alkyl, etc. , a group substituted in place of a hydrogen atom is, for example, a halogen, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted arylthio (such as phenylthio), a substituted or unsubstituted arylamino (phenylamino etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
本明細書において、置換又は非置換のアミノとしては、任意に、C1-C6アルキルで置換されていても良いアミノ等が例示される。限定はされないが、置換又は非置換のアミノとしては、アミノ、メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ、エチルメチルアミノ、シクロプロピルアミノ、シクロヘキシルアミノが挙げられる。この他に、任意に置換されたアミノとしては、ヒドラジン、C1-C6アルキル置換ヒドラジン、ベンジルアミノ、アセチルアミノ、ベンゾイルアミノ、メチルスルホニルアミノ、テトラヒドロピラニルアミノ、テトラヒドロフラニルアミノ、モルホリノアミノ、モルホリニルアミノ、ピペリジニルアミノ、ピペラジニルアミノ等が挙げられる。 As used herein, substituted or unsubstituted amino is exemplified by amino optionally substituted with C1-C6 alkyl. Substituted or unsubstituted amino include, but are not limited to, amino, methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, cyclopropylamino, cyclohexylamino. Other optionally substituted amino include hydrazine, C1-C6 alkyl substituted hydrazine, benzylamino, acetylamino, benzoylamino, methylsulfonylamino, tetrahydropyranylamino, tetrahydrofuranylamino, morpholinoamino, morpholinyl. amino, piperidinylamino, piperazinylamino and the like.
置換もしくは非置換のアシルとしては、例えば、炭素数1~7の脂肪族アシルおよびアロイルが挙げられる。具体的には、限定はされないが、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、ピバロイル、ヘキサノイル、アクリロイル、プロピオロイル、メタクリロイル、クロトノイルおよび
ベンゾイル等が例示される。
Substituted or unsubstituted acyl includes, for example, aliphatic acyl and aroyl having 1 to 7 carbon atoms. Specific examples include, but are not limited to, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl and benzoyl.
置換もしくは無置換のスルホニルとしては、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、tert-ブチルスルホニル、イソブチルスルホニル、sec-ブチルスルホニル、フェニルスルホニル、ナフチルスルホニル、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 Examples of substituted or unsubstituted sulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, phenylsulfonyl, naphthylsulfonyl, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclo hexenylsulfonyl, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like.
置換もしくは非置換のカルバモイルとしては、カルバモイル、N-メチルカルバモイル、N,N-ジメチルカルバモイル、N-エチル-N-メチルカルバモイル、N,N-ジエチルカルバモイル、N-n-プロピルアミノカルバモイル、N-イソプロピルカルバモイル、N-モルホリノカルバモイル、N-テトラヒドロフラニルカルバモイル、N-ピペリジルカルバモイル、N-テトラヒドロピラニルカルバモイル、N-ベンジルカルバモイル、N-アセチルカルバモイル、N-メチルスルホニルカルバモイル、N-(2,2,2-トリフルオロエチル)カルバモイル、N-(2-ヒドロキシ-1-メチルエチル)カルバモイル等が挙げられる。異なる態様として、カルバモイル、N-メチルカルバモイル、N,N-ジメチルカルバモイル、N-n-プロピルアミノカルバモイル、N-イソプロピルカルバモイル、N-モルホリノカルバモイル、N-テトラヒドロフラニルカルバモイル、N-ピペリジルカルバモイル、N-テトラヒドロピラニルカルバモイル、N-メチルスルホニルカルバモイル、N-(2,2,2-トリフルオロエチル)カルバモイル、N-(2-ヒドロキシ-1-メチルエチル)カルバモイル等が挙げられる。 Substituted or unsubstituted carbamoyl includes carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, Nn-propylaminocarbamoyl, N-isopropyl Carbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydropyranylcarbamoyl, N-benzylcarbamoyl, N-acetylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-tri fluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl and the like. As different embodiments, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, Nn-propylaminocarbamoyl, N-isopropylcarbamoyl, N-morpholinocarbamoyl, N-tetrahydrofuranylcarbamoyl, N-piperidylcarbamoyl, N-tetrahydro pyranylcarbamoyl, N-methylsulfonylcarbamoyl, N-(2,2,2-trifluoroethyl)carbamoyl, N-(2-hydroxy-1-methylethyl)carbamoyl and the like.
置換もしくは非置換のC3-C7シクロアルキルとしては、シクロプロピル、シクロブチル、シクロヘキシル等が例示される。 Examples of substituted or unsubstituted C3-C7 cycloalkyl include cyclopropyl, cyclobutyl, cyclohexyl and the like.
置換もしくは非置換のC3-C7シクロアルケニルとしては、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が例示される。 Examples of substituted or unsubstituted C3-C7 cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
置換もしくは非置換の非芳香族複素環式基としては、任意に、1~3個のC1-C6アルキル、C1-C6アルコキシ、アミノ、ニトロ、シアノ又はハロゲンで置換されていても良いアジリジニル、オキシラニル、チイラニル、アゼチジニル、オキセタニル、チエタニル、テトラヒドロチエニル、テトラヒドロフラニル、ピロリニル、ベンゾジオキサン、ピロリジニル、イミダゾリニル、イミダゾリジニル、オキサゾリニル、オキサゾリジニル、ピラゾリニル、ピラゾリジニル、チアゾリニル、チアゾリジニル、テトラヒドロイソチアゾリル、テトラヒドロオキサゾリル、テトラヒドロイソオキサゾリル、ピペリジニル、ピペラジニル、テトラヒドロピリジニル、ジヒドロピリジニル、ジヒドロチオピラニル、テトラヒドロピリミジニル、テトラヒドロピリダジニル、ジヒドロピラニル、テトラヒドロピラニル、テトラヒドロチオピラニル、モルホリニル、チオモルホリニル、アゼパニル、ジアゼパニル、アゼピニル、オキセパニル、アゾカニル、ジアゾカニルが例示される。 Substituted or unsubstituted non-aromatic heterocyclic groups include aziridinyl optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, oxiranyl , thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, benzodioxane, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroiso oxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl , diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl.
置換もしくは非置換のアリ一ルとしては、任意に、1~3個のC1-C6アルキル、C1-C6アルコキシ、アミノ、ニトロ、シアノ又はハロゲンで置換されていても良いC6~C14のアリールが挙げられ、より具体的には、フェニル、ナフチル、アズレニル、アントリル等が例示される。アリールは、好ましくは、フェニルである。 Substituted or unsubstituted aryl includes C6-C14 aryl optionally substituted with 1-3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen. More specific examples include phenyl, naphthyl, azulenyl, anthryl and the like. Aryl is preferably phenyl.
置換もしくは非置換のへテロアリ一ルとしては、任意に、1~3個のC1-C6アルキル、C1-C6アルコキシ、アミノ、ニトロ、シアノ又はハロゲンで置換されていても良い、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、1,2,4-オキサジアゾリル、1,3,4-オキサジアゾリル、1,2,4-チアジアゾリル、1,3,4-チアジアゾリル、トリアゾリル、テトラゾリル、トリアジニル、ベンゾチオフェニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾジオキソリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾトリアゾリル、イミダゾピリジニル、チエノピリジニル、フロピリジニル、ピロロピリジニル、ピラゾロピリジニル、オキサゾロピリジニル、チアゾロピリジニル、イミダゾピラジニル、イミダゾピリミジニル、チエノピリミジニル、フロピリミジニル、ピロロピリミジニル、ピラゾロピリミジニル、オキサゾロピリミジニル、チアゾロピリミジニル、ピラゾロトリアジニル、ナフト[2,3-b]チエニル、フェノキサチイニル、インドリル、イソインドリル、1H-インダゾリル、プリニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β-カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルが例示される。 substituted or unsubstituted heteroaryl, optionally substituted with 1 to 3 C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, cyano or halogen, thienyl, furyl, pyrrolyl , imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 - thiadiazolyl, triazolyl, tetrazolyl, triazinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzodioxolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia zolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, Examples include β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl.
本発明の誘導体において、R1、R2は、ボロン酸(‐B(OH)2)、ボロン酸エステル、又はボロン酸アミドの置換基のいずれかを表わすが、この定義におけるボロン酸エステル又はボロン酸アミドの基の例としては、R1、R2の位置において、‐B(NR71)2、又は‐B(OR71)2のような鎖状構造を有する基、又は原子Bと共に、環状構造を有する基を表す。ここで、R71は、直鎖状もしくは分岐状のC1-C10のアルキル基を表す。ここで、「直鎖状又は分岐状のC1-C10のアルキル基」というときには、炭素数1-10のいずれのアルキル基でも良い。好ましくは、直鎖状又は分岐状のC1-C8のアルキル基、より好ましくは、直鎖状又は分岐状のC1-C6のアルキル基である。これらの基としては、限定はされないが、例えば、メチル基、エチル基、イソプロピル基、ブチル基等が挙げられる。 In the derivatives of the invention, R 1 , R 2 represent any of the substituents of boronic acid (-B(OH) 2 ), boronic ester, or boronic amide, but in this definition boronic ester or boron Examples of acid amide groups include groups having a chain structure such as -B(NR 71 ) 2 or -B(OR 71 ) 2 at the positions of R 1 and R 2 , or together with atom B, cyclic represents a group having a structure. Here, R 71 represents a linear or branched C1-C10 alkyl group. Here, the term “linear or branched C1-C10 alkyl group” may be any alkyl group having 1-10 carbon atoms. A linear or branched C1-C8 alkyl group is preferred, and a linear or branched C1-C6 alkyl group is more preferred. Examples of these groups include, but are not limited to, methyl group, ethyl group, isopropyl group, butyl group, and the like.
さらに、ここでいう原子Bと共に、環状構造を有する基では、かならずしもO原子のみが介在するものではなく、N原子が介在するものであってもよい。限定はされないが、例えば、ピナコール、2,2-ジメチル-1,3-プロパンジオール、N-メチルジエタノールアミン、1-6-ジアミノナフタレン、N-メチルイミノ二酢酸、1,1,1-トリスハイドロキシメチルエタン、及びカテコールからなる群より選択されるいずれかと原子Bとで構成されるエステル又はエステル類似体で構成される基である。これらには、限定はされないが、例えば、ボロン酸ピナコールエステル、ボロン酸MIDAエステル、ボロン酸1,3-プロパンジオールエステル、ボロン酸ネオペンチルグリコールエステル、ボロン酸カテコールエステル、ボロン酸ピナンジオールエステル、ボロン酸ビスシクロヘキシルジオールエステル、ボロン酸MPMエステル、トリフルオロボレート塩、環状トリオールボレート塩、ジアミノナフタレンアミドとホウ素との環状体等が含まれる。 Furthermore, in the group having a cyclic structure together with the atom B referred to here, not only O atoms but also N atoms may intervene. Examples include, but are not limited to, pinacol, 2,2-dimethyl-1,3-propanediol, N-methyldiethanolamine, 1-6-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trishydroxymethylethane and catechol. These include, but are not limited to, boronic acid pinacol ester, boronic acid MIDA ester, boronic acid 1,3-propanediol ester, boronic acid neopentyl glycol ester, boronic acid catechol ester, boronic acid pinanediol ester, boron acid biscyclohexyl diol esters, boronic acid MPM esters, trifluoroborate salts, cyclic triol borate salts, diaminonaphthaleneamide-boron cyclics, and the like.
ここで、ホウ素原子は、限定はされないが、ホウ素10の割合が、好ましくは、75質量%以上であり、より好ましくは、80質量%以上、さらにより好ましくは、90質量%以上、特に好ましくは、95質量%以上であってもよい。 Here, the boron atom is not limited, but the ratio of boron 10 is preferably 75% by mass or more, more preferably 80% by mass or more, still more preferably 90% by mass or more, particularly preferably , 95% by mass or more.
天然のホウ素(ホウ素)には、ホウ素10とホウ素11が同位体として、ホウ素10が20%、ホウ素11が80%の割合で存在する。従って、本発明のボロノフェニルアラニンアミド誘導体の製造に先立って、質量数が10のホウ素(ホウ素10)を濃縮することも好ましい。本発明においては、例えば、ホウ素原子源として、市販されている製品を用いてもよい。市販品としては、例えば、10B濃縮ホウ酸(ステラケミファ株式会社製)を用いることができる。 In natural boron (boron), boron-10 and boron-11 are isotopes, and boron-10 is present at a ratio of 20% and boron-11 at a ratio of 80%. Therefore, it is also preferable to enrich boron with a mass number of 10 (boron 10) prior to the production of the boronophenylalanine amide derivative of the present invention. In the present invention, for example, a commercially available product may be used as the boron atom source. As a commercial product, for example, 10B concentrated boric acid (manufactured by Stella Chemifa Co., Ltd.) can be used.
ここで、ホウ素10の測定方法としては、Agilent 710(Agilent社製)を使用し、マルチ型ICP発光分光分析法(ICP-ОES)にて行うことができる。測定に使用するICP-ОESは、JISK0116に準じて調整する。 Here, as a method for measuring boron 10, Agilent 710 (manufactured by Agilent) can be used and multi-type ICP emission spectrometry (ICP-OES) can be performed. ICP-OES used for measurement is adjusted according to JISK0116.
前記化合物中、限定はされないが、R1R2は、B原子と共に、ボロン酸(B(OH)2)又は鎖状又は環状構造のボロン酸エステルが好ましく、ボロン酸(B(OH)2)又はボロン酸のピナコールエステルであることがより好ましい。 In the compound, although not limited, R 1 R 2 together with the B atom is preferably boronic acid (B(OH) 2 ) or a boronic acid ester of chain or cyclic structure, and boronic acid (B(OH) 2 ) or pinacol ester of boronic acid.
前記化合物中、限定はされないが、前記R3として、いずれか1~4個が、独立して、H、Cl、F、C1-C3アルキル、C1-C3アルコキシ、C1-C6アルキルチオ、CH2F、CHF2、又はCF3であることが特に好ましい。 In the compound, although not limited, any one to four of R 3 are independently H, Cl, F, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 alkylthio, CH 2 F , CHF 2 or CF 3 are particularly preferred.
前記化合物中、限定はされないが、前記R4はH、C1-C6アルキル、であることが好ましい。 In said compound, said R 4 is preferably, but not limited to, H, C1-C6 alkyl.
前記化合物中、R5は、H、C1-C6アルキル、C3-C7シクロアルキル、C1-C6アルコキシ、ハロゲン置換C1-C3アルキル、置換又は無置換のフェニル(置換の場合は、限定はされないが、ハロゲン、C1-C3アルキル、C1-C3アルコキシ、ニトロ等で置換されているフェニルであることが好ましい)、ナフチル、置換又は無置換のフェニルで置換されているC1-C6アルキル(ここで、置換フェニルというときには、限定はされないが、ハロゲン、C1-C3アルキル、C1-C3アルコキシ、ニトロ等で置換されているフェニルであることが好ましい)、置換又は無置換のフェニルで置換されているC1-C6アルコキシ(ここで、置換フェニルというときには、限定はされないが、ハロゲン、C1-C3アルキル、C1-C3アルコキシ、ニトロ等で置換されていることが好ましい)、チエニル、フリル、ピリミジン、チエニル置換C1-C6アルキル、フリル置換C1-C6アルキル、ピリミジン置換C1-C6アルキル、フェニルチオ置換C1-C6アルキル、フェニルアミノ置換C1-C6アルキル、ベンゾジオキソリル、ジヒドロベンゾジオキシン、又はR4とR5がN原子と共にC3-C7ヘテロシクロアルキル、であることが好ましい。ここで、R4とR5がN原子と共にC3-C7ヘテロシクロアルキルを形成する場合は、該C3-C7ヘテロシクロアルキルとしては、限定はされないが、モルフォリノ、ピロリジン等が挙げられる。 In the above compounds, R 5 is H, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C3 alkyl, substituted or unsubstituted phenyl (if substituted, but not limited to phenyl substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), naphthyl, C1-C6 alkyl substituted with substituted or unsubstituted phenyl (where substituted phenyl phenyl substituted with, but not limited to, halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), C1-C6 alkoxy substituted with substituted or unsubstituted phenyl (here, substituted phenyl is not limited, but preferably substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, etc.), thienyl, furyl, pyrimidine, thienyl-substituted C1-C6 alkyl , furyl-substituted C1-C6 alkyl, pyrimidine-substituted C1-C6 alkyl, phenylthio-substituted C1-C6 alkyl, phenylamino-substituted C1-C6 alkyl, benzodioxolyl, dihydrobenzodioxin, or R 4 and R 5 together with an N atom are C3 -C7 heterocycloalkyl, preferably. Here, when R 4 and R 5 together with the N atom form a C3-C7 heterocycloalkyl, the C3-C7 heterocycloalkyl includes, but is not limited to morpholino, pyrrolidine and the like.
前記化合物中、限定はされないが、前記R6は、H又はC1-C6アルキル、又はR6と隣接するメチレンと共にベンゼン環に縮合する形で環構造を形成し、ここで、環構造は、非置換のC5-C7シクロアルキルであることが好ましい。このうち、R6は、H、メチル又はエチルを表すことがより好ましい。 In said compound, said R 6 is, but not limited to, H or C1-C6 alkyl, or together with the methylene adjacent to R 6 forms a ring structure in a form fused to a benzene ring, wherein the ring structure is non- Preferred is substituted C5-C7 cycloalkyl. Among these, R 6 more preferably represents H, methyl or ethyl.
本発明のボロノフェニルアラニンアミド誘導体のうち、特に好ましいのは以下の化合物からなる群より選択される1種又はその塩である。
(S)-(4-(2-アミノ-3-(エチルアミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-((2,2,2-トリフルオロエチル)アミノ)プロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-(p-トリルアミノ)プロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-(m-トリルアミノ)プロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((3,4-ジメチルフェニル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((4-メトキシフェニル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((3,5-ジメトキシフェニル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((3-メトキシフェニル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)‐(4‐(2‐アミノ‐3‐(ベンゾ[d][1,3]ジオキソール‐5‐イルアミノ)‐3‐オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((2,3-ジヒドロキシベンゾ[b][1,4]ジオキシン-6-イル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-(フェネチルアミノ)プロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((4-メトキシフェネチル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((3-メトキシフェネチル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-((4-フルオロフェネチル)アミノ)-3-オキソプロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-((2-フェノキシエチル)アミノ)プロピル)フェニル)ボロン酸;
(S)-(4-(2-アミノ-3-オキソ-3-((3-フェノキシプロピル)アミノ)プロピル)フェニル)ボロン酸;及び
(S)-(4-(2-アミノ-3-オキソ-3-(ピリジン-2-イルアミノ)プロピル)フェニル)ボロン酸。
Among the boronophenylalanine amide derivatives of the present invention, particularly preferred are one selected from the group consisting of the following compounds or a salt thereof.
(S)-(4-(2-amino-3-(ethylamino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(p-tolylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(m-tolylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3,4-dimethylphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3,5-dimethoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((2,3-dihydroxybenzo[b][1,4]dioxin-6-yl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-(phenethylamino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((3-methoxyphenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-((4-fluorophenethyl)amino)-3-oxopropyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((2-phenoxyethyl)amino)propyl)phenyl)boronic acid;
(S)-(4-(2-amino-3-oxo-3-((3-phenoxypropyl)amino)propyl)phenyl)boronic acid; and (S)-(4-(2-amino-3-oxo) -3-(Pyridin-2-ylamino)propyl)phenyl)boronic acid.
本発明における「薬学的に許容できる塩」とは、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。無機塩基との塩の好適な例としては、例えばナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;ならびにアルミニウム塩、アンモニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えばトリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、N,N'-ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えばギ酸、酢酸、トリフルオロ酢酸、フマール酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えばアルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えばアスパラギン酸、グルタミン酸等との塩が挙げられる。 The "pharmaceutically acceptable salt" in the present invention includes salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. . Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Preferable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p - salts with toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. be done.
〔ボロノフェニルアラニンアミド誘導体の製造方法]
本発明において、新規なボロノフェニルアラニンアミド誘導体の製造方法は、限定はされず、通常のアミノ酸合成方法が用いられる。限定はされないが、特に好ましい方法は、例えば、以下のような方法であり得る。
まず、下記一般式(II)で表される有機ハロゲン化物に保護アミノ酸を、有機溶媒、塩基性水溶液、相関移動触媒の存在下にて反応させる。
[Method for producing boronophenylalanine amide derivative]
In the present invention, the method for producing the novel boronophenylalanine amide derivative is not limited, and conventional methods for synthesizing amino acids are used. Although not limited, a particularly preferred method may be, for example, the following method.
First, an organic halide represented by the following general formula (II) is reacted with a protected amino acid in the presence of an organic solvent, a basic aqueous solution, and a phase transfer catalyst.
X1、及びX2は、独立してハロゲン(F、Cl、Br、I)を表すものとする。
さらに、式(II)中、ベンゼン環は、X1が存在する箇所以外で任意に1-4個の置換基R3で置換されていてもよい。
X 1 and X 2 shall independently represent halogen (F, Cl, Br, I).
Additionally, in formula (II), the benzene ring may optionally be substituted with 1-4 substituents R 3 , except where X 1 occurs.
ここで、式(II)で表される有機ハロゲン化物としては、公知の方法で調製した化合物をそのまま使用するか、又は市販されている製品を使用することもできる。 Here, as the organic halide represented by formula (II), a compound prepared by a known method can be used as it is, or a commercially available product can be used.
このうち、例えば4-ヨードベンジルブロミド、4-ブロモ-2-フルオロベンジルブロミドは、東京化成工業株式会社やCombi-Blocksから入手可能である。4-ブロモ-3-フルオロベンジルブロミド、1-ブロモ-4-(ブロモメチル)-2,3-ジフルオロベンゼン、4-ブロモ-1-(ブロモメチル)-2-メトキシベンゼン、4-ブロモ-1-(ブロモメチル)-2-ニトロベンゼン、4-ブロモ-1-(ブロモメチル)-2-クロロベンゼン、4-ブロモ-1-(ブロモメチル)-2-(トリフルオロメチル)ベンゼン、4-ブロモ-1-(ブロモメチル)-2-(トリフルオロメチル)ベンゼン、1-ブロモ-4-(ブロモメチル)-2-メチルベンゼン、は、Combi-Blocksより入手可能である。4-ブロモ-1-(ブロモメチル)-2-メチルベンゼン、4-ブロモ-2,6-ジフルオロベンジルブロミドは、Fluorochem Ltd.より入手可能である。 Among these, for example, 4-iodobenzyl bromide and 4-bromo-2-fluorobenzyl bromide are available from Tokyo Kasei Kogyo Co., Ltd. and Combi-Blocks. 4-bromo-3-fluorobenzyl bromide, 1-bromo-4-(bromomethyl)-2,3-difluorobenzene, 4-bromo-1-(bromomethyl)-2-methoxybenzene, 4-bromo-1-(bromomethyl )-2-nitrobenzene, 4-bromo-1-(bromomethyl)-2-chlorobenzene, 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, 4-bromo-1-(bromomethyl)-2 -(trifluoromethyl)benzene, 1-bromo-4-(bromomethyl)-2-methylbenzene, are available from Combi-Blocks. 4-bromo-1-(bromomethyl)-2-methylbenzene, 4-bromo-2,6-difluorobenzyl bromide are available from Fluorochem Ltd.; more available.
5-ブロモ-2-(ブロモメチル)ベンゾニトリルは、例えば、東京化成工業株式会社より入手可能な5-ブロモ-2-メチルベンゾニトリルから調製でき、1-ブロモ-4-(ブロモメチル)-2-クロロ-5-フルオロベンゼン、5-ブロモ-2-メチルチオアニソールは、Combi-Blocksより入手可能な4-ブロモ-5-クロロ-2‐フルオロトルエンから調製できる。これらの化合物は、例えば、市販の化合物に、2,2‘-アゾビス(イソブチロニトリル)共存下N-ブロモスクシンイミドを作用させることで調製可能である。 5-bromo-2-(bromomethyl)benzonitrile can be prepared, for example, from 5-bromo-2-methylbenzonitrile available from Tokyo Chemical Industry Co., Ltd., followed by 1-bromo-4-(bromomethyl)-2-chloro -5-fluorobenzene, 5-bromo-2-methylthioanisole can be prepared from 4-bromo-5-chloro-2-fluorotoluene available from Combi-Blocks. These compounds can be prepared, for example, by reacting a commercially available compound with N-bromosuccinimide in the presence of 2,2'-azobis(isobutyronitrile).
4-(ブロモメチル)-1-ヨード-2-ニトロベンゼンは、例えば、Combi-Blocksより入手可能な(4-ヨード-3-ニトロ-フェニル)-メタノールに対し、臭化水素酸で臭素化することで調製可能である。 4-(bromomethyl)-1-iodo-2-nitrobenzene can be obtained, for example, from (4-iodo-3-nitro-phenyl)-methanol available from Combi-Blocks by bromination with hydrobromic acid. can be prepared.
その他のベンジルブロミドは、市販品から入手可能であり、入手不可のものは、例えば対応する置換基を有するトルエンに対し、2,2‘-アゾビス(イソブチロニトリル)共存下N-ブロモスクシンイミドを作用させることで調製可能であり、もしくは対応する置換基を有するベンズアルデヒドや安息香酸メチルを水素化ホウ素ナトリウムや水素化アルミニウムリチウムで還元してベンジルアルコールを得た後、臭化水素酸や三臭化りんで臭素化することで調製可能である。 Other benzyl bromides are available from commercial products, and those that are not available are, for example, N-bromosuccinimide in the presence of 2,2'-azobis(isobutyronitrile) for toluene having a corresponding substituent. Alternatively, benzaldehyde or methyl benzoate having a corresponding substituent can be reduced with sodium borohydride or lithium aluminum hydride to give benzyl alcohol, followed by hydrobromic acid or tribromide. It can be prepared by bromination with phosphorus.
式(II)で表される有機ハロゲン化物と保護アミノ酸の反応は、有機溶媒、塩基性水溶液、相関移動触媒の存在下にて進めることができる。保護アミノ酸としては、p-クロロベンズアルデヒドイミン又はベンゾフェノンイミン等が例示される。好ましくは、下記の構造のp-クロロベンズアルデヒドイミンであり得る。
ここで、R6は、H又は置換されていてもよいC1-C6アルキルを表す。 Here, R 6 represents H or optionally substituted C1-C6 alkyl.
ここで、使用する有機溶媒は、限定はされないが、好ましくは、トルエン、ベンゼン、キシレン、メシチレン、エチルエーテル、イソプロピルエーテル、テトラヒドロフラン、ジオキサン、酢酸エチル、酢酸イソプロピル、シクロペンチルメチルエーテル、メチルt-ブチルエーテルなどが挙げられる。 Here, the organic solvent used is not limited, but preferably toluene, benzene, xylene, mesitylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, methyl t-butyl ether, etc. is mentioned.
塩基性水溶液は、好ましくは、水酸化カルシウム、水酸化セシウム、水酸化カリウム等の水溶液である。 The basic aqueous solution is preferably an aqueous solution of calcium hydroxide, cesium hydroxide, potassium hydroxide, or the like.
相関移動触媒は、例えば丸岡試薬であり得る。丸岡試薬としては、限定はされないが、好ましくは、(R)-4,4-ジブチル-2,6-ビス(3,4,5-トリフルオロフェニル)-4,5-ジヒドロ-3H-ジナフト[2,1-c:1′,2′-e]アゼピニウムブロミド、(R)-4,4-ジブチル-2,6-ビス(3,4,5-トリフルオロフェニル)-4,5-ジヒドロ-3H-ジナフト[2,1-c:1′,2′-e]アゼピニウムブロミド、(S)-4,4-ジブチル-2,6-ビス(3,4,5-トリフルオロフェニル)-4,5-ジヒドロ-3H-ジナフト[2,1-c:1′,2′-e]アゼピニウムブロミド、(S)-4,4-ジブチル-2,6-ビス(3,4,5-トリフルオロフェニル)-4,5-ジヒドロ-3H-ジナフト[2,1-c:1′,2′-e]アゼピニウムブロミド等を用いることができる。 The phase transfer catalyst can be, for example, Maruoka's reagent. The Maruoka reagent is not limited, but preferably (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho [ 2,1-c: 1′,2′-e]azepinium bromide, (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5- Dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl )-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (S)-4,4-dibutyl-2,6-bis(3,4 ,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide and the like can be used.
この時の反応温度は、好ましくは、-20℃~10℃の間であり、反応時間は、1時間から60時間程度であり得る。 The reaction temperature at this time is preferably between −20° C. and 10° C., and the reaction time can be about 1 hour to 60 hours.
反応終了後、トルエン等の有機溶媒で抽出し、適宜、洗浄、乾燥、濾過工程に供することができる。 After completion of the reaction, the product can be extracted with an organic solvent such as toluene, and subjected to washing, drying and filtration steps as appropriate.
次にこのような反応生成物に、溶媒を加え、酸と反応させる。ここで、溶媒としては、エーテル系溶媒を使用することが好ましい。ここで、エーテル系溶媒としては、限定はされないが、ジエチルエーテル、テトラヒドロフラン(THF)、2-メチルテトラヒドロフラン、ジオキサン、シクロペンチルメチルエーテル、グライム、ジグライム等が例示される。本発明において、特に好ましくは、テトラヒドロフランが用いられる。 A solvent is then added to such reaction product and reacted with the acid. Here, as the solvent, it is preferable to use an ether solvent. Examples of the ether solvent include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentylmethyl ether, glyme, and diglyme. Tetrahydrofuran is particularly preferably used in the present invention.
酸としては、クエン酸、酢酸、トリクロロ酢酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸、トルエンスルホン酸、メタンスルホン酸のような有機酸、塩酸、硫酸、硝酸、りん酸のような無機酸等が挙げられる。 Examples of acids include organic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. be done.
反応は、好ましくは、0℃から50℃の範囲の温度で行われる。 The reaction is preferably carried out at a temperature in the range 0°C to 50°C.
前記反応時間は、1~10時間程度であり、より好ましくは、2~8時間であり、さらに好ましくは、3~6時間である。 The reaction time is about 1 to 10 hours, preferably 2 to 8 hours, still more preferably 3 to 6 hours.
得られた化合物のアミノ基を常法により保護する。保護基は、限定はされないが、例えば、カルバメート系保護基、アミド系保護基、アルキル保護基が好ましく用いられる。このようなカルバメート系保護基としては、tert-ブトキシカルボニル基(Boc)、ベンジルオキシカルボニル基(Cbz)、9-フルオレニルメチルオキシカルボニル基(Fmoc)、2,2,2-トリクロロエトキシカルボニル基(Troc)等が挙げられ、アミド系保護基としては、アセチル基、ベンゾイル基等が挙げられ、アルキル保護基としては、ベンジル基等が挙げられる。 The amino group of the obtained compound is protected by a conventional method. Although the protecting group is not limited, for example, a carbamate-based protecting group, an amide-based protecting group, and an alkyl protecting group are preferably used. Such carbamate-based protective groups include tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), 2,2,2-trichloroethoxycarbonyl group (Troc) and the like, the amide-based protecting group includes acetyl group, benzoyl group and the like, and the alkyl protecting group includes benzyl group and the like.
次に、上記のようにして得られる化合物又はボロン酸又はボロノ基を有するアミン体に、アミン化合物を溶媒中で、縮合剤と共に反応させて縮合させる。 Next, the compound obtained as described above or the amine compound having a boronic acid or borono group is condensed by reacting the amine compound with a condensing agent in a solvent.
縮合剤としては、限定はされないが、例えば、1-[3-(ジメチルアミノ)プロピル]-3-エチルカルボジイミド、1-[3-(ジメチルアミノ)プロピル]-3-エチルカルボジイミド塩酸塩、N,N’-ジシクロヘキシルカルボジイミド、N,N’-ジイソプロピルカルボジイミド、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(HATU」)、ジフェニルホスホリルアジド等が挙げられる。 Examples of condensing agents include, but are not limited to, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU"), diphenyl and phosphoryl azide.
上記反応は、塩基存在下で反応を行うこともできる。塩基としては、例えば、TEA、DIPEA,ピリジン等の有機塩基を挙げることが出来る。 The above reaction can also be carried out in the presence of a base. Examples of bases include organic bases such as TEA, DIPEA and pyridine.
上記反応は、ラセミ化抑制のために添加剤を用いることもできる。添加剤としては、例えば、1-ヒドロキシベンゾトリアゾール、1-ヒドロキシベンゾトリアゾール一水和物、1-ヒドロキシ-7-アザベンゾトリアゾール、N-ヒドロキシ-5-ノルボルネン-2,3-ジカルボキシイミド、3,4-ジヒドロ-3-ヒドロキシ-4-オキソ-1,2,3-ベンゾトリアジン、N-ヒドロキシコハク酸イミドなどが挙げられる。 Additives can also be used in the above reaction to suppress racemization. Examples of additives include 1-hydroxybenzotriazole, 1-hydroxybenzotriazole monohydrate, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, 3 ,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, N-hydroxysuccinimide and the like.
溶媒としては、限定はされないが、ハロゲン系溶媒、エーテル系溶媒、アミド類、ニトリル類、又はこれらの混合溶媒が用いられる。 Examples of the solvent include, but are not limited to, halogen-based solvents, ether-based solvents, amides, nitriles, or mixed solvents thereof.
ハロゲン系溶媒としては、限定はされないが、ジクロロメタン、クロロホルム、四塩化炭素等が例示される。 Examples of halogen-based solvents include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, and the like.
エーテル系溶媒としては、限定はされないが、ジエチルエーテル、テトラヒドロフラン(THF)、2-メチルテトラヒドロフラン、ジオキサン、シクロペンチルメチルエーテル、グライム、ジグライム等が例示される。 Examples of ether solvents include, but are not limited to, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, cyclopentylmethyl ether, glyme, and diglyme.
アミド類の溶媒としては、限定はされないが、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)等が例示される。 Solvents for amides include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), and the like.
ニトリル類の溶媒としては、アセトニトリル、プロピオニトリル等が例示される。 Examples of nitrile solvents include acetonitrile and propionitrile.
反応温度は、限定はされないが、-78℃~200℃が好ましく、-20℃~50℃がより好ましい。 The reaction temperature is not limited, but preferably -78°C to 200°C, more preferably -20°C to 50°C.
反応時間は、限定はされないが、通常、1~24時間程度である。 Although the reaction time is not limited, it is usually about 1 to 24 hours.
次に、得られた化合物に、必要に応じて、ホウ素化合物を、溶媒中、パラジウム触媒、有機リン化合物及び塩基の存在下、反応させる。既にボロン酸又はボロノ基を有する化合物であれば、本工程は省略し得る。 Next, the resulting compound is optionally reacted with a boron compound in a solvent in the presence of a palladium catalyst, an organic phosphorus compound and a base. This step can be omitted if the compound already has a boronic acid or borono group.
ここで、パラジウム触媒は、限定はされないが、例えば、酢酸パラジウム(II)、塩化パラジウム(II)、及びトリス(ジベンジリデンアセトン)ジパラジウム(0)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物、テトラキス(トリフェニルホスフィン)パラジウム(0)等が挙げられる。 Here, palladium catalysts include, but are not limited to, palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino )ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) and the like.
有機リン化合物は、限定はされないが、例えば、トリフェニルホスフィン、トリシクロヘキシルホスフィン、1,1’-ビス(ジフェニルホスフィノ)フェロセン、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、及び2-ジシクロヘキシルホスフィノ-2’-(N,N-ジメチルアミノ)ビフェニル等が挙げられる。 Organic phosphorus compounds include, but are not limited to, triphenylphosphine, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl and the like.
塩基としては、限定はされないが、例えば、酢酸カリウム、酢酸ナトリウム、炭酸ナトリウム、炭酸セシウム、炭酸カリウム、及び炭酸水素ナトリウム等が挙げられる。 Examples of bases include, but are not limited to, potassium acetate, sodium acetate, sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, and the like.
ホウ素化合物としては、ホウ酸エステル又はホウ酸アミドが例示され、好ましくは、B(OR)3、B(NR)3、B(OR)2(NR)、(RO)2B-B(OR)2、又はB(OR)(NR)2(Rは、直鎖状又は分岐状のC1-C10アルキル基、フェニル基、又はベンジル基)で表される化合物等を指す。さらに、このうち、特に好ましくは、(RO)2B-B(OR)2で表される化合物が用いられる。ここで、「直鎖状又は分岐状のC1-C10のアルキル基」というときには、炭素数1-10のいずれのアルキル基でも良いが、好ましくは、直鎖状又は分岐状のC1-C8のアルキル基、より好ましくは、直鎖状又は分岐状のC1-C6のアルキル基である。これらの基としては、限定はされないが、例えば、メチル基、エチル基、イソプロピル基、ブチル基などが挙げられる。ホウ素化合物として、限定はされないが、代表的には、ビス(ピナコラート)ジボロンが挙げられる。 Examples of boron compounds include borate esters and borate amides, preferably B(OR) 3 , B(NR) 3 , B(OR) 2 (NR), (RO) 2 BB(OR) 2 , or B(OR)(NR) 2 (R is a linear or branched C1-C10 alkyl group, phenyl group, or benzyl group). Furthermore, among these, a compound represented by (RO) 2 BB(OR) 2 is particularly preferably used. Here, the term "linear or branched C1-C10 alkyl group" may be any alkyl group having 1 to 10 carbon atoms, but preferably linear or branched C1-C8 alkyl groups, more preferably linear or branched C1-C6 alkyl groups. Examples of these groups include, but are not limited to, methyl groups, ethyl groups, isopropyl groups, butyl groups, and the like. A representative example of the boron compound is, but not limited to, bis(pinacolato)diboron.
溶媒としては、限定はされないが、例えば1,4-ジオキサン、テトラヒドロフラン、1,2-ジメトキシエタン等のエーテル系溶媒;トルエン等の炭化水素系溶媒;及びN,N-ジメチルホルムアミド、ジメチルスルホキシド等の極性溶媒が例示される。好ましい溶媒は、ジメチルスルホキシドが挙げられる。反応温度は、例えば20℃から160℃であり、好ましくは60℃から120℃である。 Examples of the solvent include, but are not limited to, ether solvents such as 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and N,N-dimethylformamide, dimethylsulfoxide, and the like. Polar solvents are exemplified. Preferred solvents include dimethylsulfoxide. The reaction temperature is, for example, 20°C to 160°C, preferably 60°C to 120°C.
次に、得られた化合物を順次脱保護又はそのまま次の工程に供する。脱保護は、常法に従うが、例えば、加水分解や接触水素化、脱炭酸、酸化によって行うことができる。 Next, the obtained compounds are sequentially deprotected or directly subjected to the next step. Deprotection can be carried out by conventional methods, such as hydrolysis, catalytic hydrogenation, decarboxylation, and oxidation.
製造方法の各工程において、精製は、常法に従い、また、適宜改変し得る。 In each step of the production method, purification follows a conventional method and can be modified as appropriate.
特に化合物がラセミ体である場合には、そのまま用いることもできるし、例えば、ホウ素中性子捕捉療法に使用する為の好ましい化合物を得る為に、R体又はS体の光学純度を高めることもできる。 Especially when the compound is racemic, it can be used as is, or the optical purity of the R- or S-form can be enhanced in order to obtain the preferred compound for use, for example, in boron neutron capture therapy.
光学分割は公知の手法を適宜用いてもよいが、例えば、加水分解工程、エステル化工程を経て、光学分割(αキモトリプシンなどを使用)する方法の他、加水分解工程を経て、アシラーゼを使用する簡略した工程を含む簡略化した方法を採用することもできる。 For the optical resolution, a known method may be used as appropriate. For example, a hydrolysis step, an esterification step, followed by an optical resolution (using α-chymotrypsin or the like), or a hydrolysis step followed by an acylase. A simplified method including simplified steps can also be adopted.
〔BNCT(ホウ素中性子捕捉療法)用薬剤〕
本発明のボロノフェニルアラニンアミド誘導体は、上記の化合物あるいは薬学的に許容できる塩の形態でそのまま、又は薬学的に許容できるキャリアーと混合して当業者に公知の製剤の形で、あるいはマイクロ/ナノパーティクルに封入等の形で、BNCTに好都合に用いられうる。
[Drug for BNCT (Boron Neutron Capture Therapy)]
The boronophenylalanine amide derivative of the present invention can be used as it is in the form of the above compound or a pharmaceutically acceptable salt, or mixed with a pharmaceutically acceptable carrier in the form of formulations known to those skilled in the art, or micro/nano It can be conveniently used for BNCT in the form of encapsulation in particles or the like.
本発明のボロノフェニルアラニンアミド誘導体製剤を用いる治療は、任意の適当な投与経路で、ボロノフェニルアラニンアミド誘導体が標的腫瘍中に蓄積するような方法で、投与することによって行われる。ボロノフェニルアラニンアミド誘導体は放射線照射前に腫瘍に濃縮することが好ましく、放射線照射前の腫瘍:血液比が、少なくとも1.5以上:1であり、好ましくは、2以上:1である。ボロノフェニルアラニンアミド誘導体は一度に投与することもできるし、持続投与することもできる。場合によって、分けて投与することもできる。腫瘍内に化合物が望ましく蓄積した後、その部位に有効量の低エネルギー中性子線(例えば、熱外中性子線)を照射する。皮膚を通してその部位を照射することができるし、あるいはその部位を照射前に完全にあるいは部分的に露出することもできる。ボロノフェニルアラニンアミド誘導体の投与とそれに続く放射線照射を必要に応じて繰り返すことができる。所望であれば、腫瘍を外科的に可能な程度にまで縮小させる為に、ボロノフェニルアラニンアミド誘導体を使った治療を行い、その後、外科的処置を行うことができる。あるいは、外科的処置を行った後、残りの腫瘍を本発明のボロノフェニルアラニンアミド誘導体を使って破壊する。もう1つの態様として、患者に適当量のボロノフェニルアラニンアミド誘導体を投与し、天然に存在する中性子放射物質である252カリフォルニウムの有効量で照射する。これは腫瘍中に挿入し、適当な時間に取り出すことが好ましい。 Treatment with the boronophenylalanine amide derivative formulations of the present invention is effected by administration by any suitable route of administration and in such a manner that the boronophenylalanine amide derivative accumulates in the target tumor. The boronophenylalanine amide derivative is preferably concentrated in the tumor prior to irradiation and has a tumor:blood ratio of at least 1.5:1, preferably 2:1 or greater, prior to irradiation. The boronophenylalanine amide derivative can be administered once or continuously. In some cases, it can be administered separately. After the desired accumulation of the compound within the tumor, the site is irradiated with an effective dose of low energy neutrons (eg, epithermal neutrons). The site can be irradiated through the skin, or the site can be fully or partially exposed prior to irradiation. Administration of the boronophenylalanine amide derivative followed by irradiation can be repeated as necessary. If desired, treatment with the boronophenylalanine amide derivative can be followed by surgery to shrink the tumor to a surgically feasible extent. Alternatively, after surgical treatment, the remaining tumor is destroyed using the boronophenylalanine amide derivatives of the invention. In another embodiment, the patient is administered an appropriate amount of the boronophenylalanine amide derivative and irradiated with an effective amount of 252 californium, a naturally occurring neutron emitter. It is preferably inserted into the tumor and removed at the appropriate time.
ここで、腫瘍の種類は特に限定されないが、神経膠芽腫および悪性神経膠腫等を含む脳腫瘍、その他頭頸部がん、悪性黒色腫、乳がん、あるいは前立腺がん等が特に好適な対象となり得る。その他、肺がん、子宮がん、腎臓がん、肝臓がん等の上皮細胞がん、各種肉腫等も対象となり得る。 Here, the type of tumor is not particularly limited, but brain tumors including glioblastoma, malignant glioma, etc., head and neck cancer, malignant melanoma, breast cancer, prostate cancer, etc. can be particularly suitable targets. . In addition, lung cancer, uterine cancer, kidney cancer, epithelial cell carcinoma such as liver cancer, various sarcomas, and the like can also be targeted.
本発明のボロノフェニルアラニンアミド誘導体の投与は、経口および非経口でなされ得る。非経口投与の場合、動脈内(例えば、頚動脈を介する)、筋肉内、皮下、髄内、クモ膜下腔内、脳室内、静脈内、腹腔内、または鼻孔内へなされうる。 Administration of the boronophenylalanine amide derivatives of the present invention can be oral and parenteral. Parenteral administration can be intraarterial (eg, via the carotid artery), intramuscular, subcutaneous, intramedullary, intrathecal, intracerebroventricular, intravenous, intraperitoneal, or intranasal.
製剤は、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤等のいずれの形態にもなり得る。また、その剤型に応じ、製剤学的に公知の手法により、適切な添加剤および/または薬学的に受容可能なキャリアーと混合して、単独で、あるいは他の薬剤と組み合わせて患者に投与され得る。添加剤は、例えば賦形剤 ;崩壊剤;結合剤;滑沢剤;希釈剤;リン酸、クエン酸、コハク酸、酢酸、および他の有機酸またはそれらの塩のような緩衝剤;等張化剤;防腐剤;湿潤剤;乳化剤;分散剤;安定化剤;溶解補助剤;アスコルビン酸のような抗酸化剤;低分子量(約10残基未満の)ポリペプチド(例えば、ポリアルギニンまたはトリペプチド);タンパク質(例えば、血清アルブミン、ゼラチン、またはイムノグロブリン);親水性ポリマー(例えば、ポリビニルピロリドン);アミノ酸(例えば、グリシン、グルタミン酸、アスパラギン酸、またはアルギニン);単糖、二糖および他の炭水化物(セルロースまたはその誘導体、グルコース、マンノース、またはデキストリンを含む);キレート剤(例えば、EDTA);糖アルコール(例えば、マンニトールまたはソルビトール);対イオン(例えば、ナトリウム);および/または非イオン性界面活性剤(例えば、ポリソルベート、ポロキサマー)、等が挙げられる。これらの医薬品添加物と適宜混合または希釈・溶解することにより調剤することができる。好ましく用いられ得るキャリアーは、限定はされないが、薬学的に不活性な水系のキャリアーである。そのようなキャリアーとしては生理食塩水、緩衝化生理食塩水、デキストロース、および水等が含まれる。本発明の一実施形態において、薬学的に受容可能なキャリアーは薬学的に不活性である。適切な添加剤および/または薬学的に受容可能なキャリアーは、使用された投薬量および濃度においてレシピエントに対して非毒性である。製剤で特に好ましいものは、水系キャリアーとともに調製される注射剤である。 Formulations can be in any form, such as powders, granules, fine granules, dry syrups, tablets, capsules, injections, and liquids. In addition, depending on the dosage form, it may be administered to the patient alone or in combination with other drugs, mixed with an appropriate additive and/or a pharmaceutically acceptable carrier, according to a pharmaceutically known method. obtain. Additives include, for example, excipients; disintegrants; binders; lubricants; diluents; emulsifiers; dispersing agents; stabilizing agents; solubilizing agents; antioxidants such as ascorbic acid; proteins (eg, serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (eg, polyvinylpyrrolidone); amino acids (eg, glycine, glutamic acid, aspartic acid, or arginine); monosaccharides, disaccharides and other carbohydrates (including cellulose or its derivatives, glucose, mannose, or dextrins); chelating agents (eg, EDTA); sugar alcohols (eg, mannitol or sorbitol); counterions (eg, sodium); and/or nonionic interfaces. active agents (eg, polysorbates, poloxamers), and the like. It can be prepared by appropriately mixing, diluting and dissolving with these pharmaceutical excipients. Carriers that can be preferably used are, but are not limited to, pharmaceutically inert aqueous carriers. Such carriers include saline, buffered saline, dextrose, water and the like. In one embodiment of the invention, the pharmaceutically acceptable carrier is pharmaceutically inert. Suitable excipients and/or pharmaceutically acceptable carriers are nontoxic to recipients at the dosages and concentrations employed. A particularly preferred formulation is an injection prepared with an aqueous carrier.
処方および投与のための技術は、例えば、日本薬局方の最新版および最新追補、「REMINGTON’S PHARMACEUTICAL SCIENCES」(Maack Publishing Co.Easton,PA)の最終版に記載されている。 Techniques for formulation and administration are described, for example, in the latest edition and latest supplement of the Japanese Pharmacopoeia, final edition of "REMINGTON'S PHARMACEUTICAL SCIENCES" (Maack Publishing Co. Easton, PA).
本発明のボロノフェニルアラニンアミド誘導体の製剤は、目的の薬剤が意図する目的を達成するのに有効な量で含有される薬剤であり、「治療的有効量」または「薬理学的有効量」は当業者に十分に認識され、薬理学的結果を生じるために有効な薬剤の量をいう。治療的有効用量の決定は十分に当業者に知られている。 The formulation of the boronophenylalanine amide derivative of the present invention is a drug containing an amount effective to achieve the intended purpose of the target drug, and a "therapeutically effective amount" or "pharmacologically effective amount" is It is well recognized by those skilled in the art and refers to the amount of an agent effective to produce a pharmacological result. Determination of a therapeutically effective dose is well known to those skilled in the art.
治療的有効量とは、ここでは、投与後の放射線照射により疾患の状態を軽減する薬剤の量をいう。このような化合物の治療効果および毒性は、細胞培養または実験動物における標準的な薬学的手順によって決定され得る。用量は、好ましくは、毒性をほとんどまたは全くともなわないED50を含む循環濃度の範囲内にある。この用量は、使用される投与形態、患者の感受性、および投与経路に依存してこの範囲内で変化する。一例として、投与量は、年齢その他の患者の条件、疾患の種類、使用する複合体の種類等により適宜選択される。好ましい用量は、限定はされないが、5~1000mg/kgとなるように1度の治療に、投与することができる。特に、処置すべき被験者の体重1kg当たり誘導体5~500mg、より好ましくは、6~480mgとすることもできる。 A therapeutically effective amount, as used herein, refers to that amount of an agent that reduces the disease state upon administration followed by irradiation. Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. Dosages preferably lie within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage will vary within this range depending on the dosage form used, patient sensitivity, and route of administration. For example, the dosage is appropriately selected depending on the age and other conditions of the patient, the type of disease, the type of conjugate to be used, and the like. A preferred dose is, but is not limited to, 5-1000 mg/kg can be administered per treatment. In particular, it may be 5-500 mg, more preferably 6-480 mg, of the derivative per kg of body weight of the subject to be treated.
〔放射性同位体を含有する診断薬]
本発明のボロノフェニルアラニンアミド誘導体は、放射性同位体を含む薬剤として調製することもできる。放射性同位体射能を含む薬剤として調製する場合には、限定はされないが、典型的には、化合物中に含まれるF原子として、18Fを用いること、化合物中に含まれるI原子として、131I、123Iを用いること、又は化合物中に含まれるC原子として11Cを用いることができる。これらの放射性同位体の位置としては、R3のいずれかの位置か、R4又はR5にアリール又はヘテロアリールを含む場合には、その置換基として導入することができる。このようにして得られる化合物を、例えば、RI検査や核医学検査に用いることが可能である。これらは、限定はされないが、シンチグラフィの断層撮影、SPECT(Single Photon Emission Computed Tomography)やPET(Positron Emission Tomography (陽電子放出断層撮影)用の薬剤を含む。すなわち、対象に対して、放射能を含む本発明のボロノフェニルアラニンアミド誘導体をPET用薬剤又はSPECT用薬剤として投与し、治療前に画像を取得し、誘導体の体内集積分布、腫瘍組織/正常組織存在比(T/N比)等の情報を得ることができる。これらの情報を基にBNCTの治療効果を事前に想定し、研究または治療計画を策定することも可能である。なお、投与態様その他は、〔BNCT(ホウ素中性子捕捉療法)用薬剤〕の項で記載した内容に準じる。
[Diagnostic Agent Containing Radioisotope]
The boronophenylalanine amide derivatives of the present invention can also be prepared as a radioisotope-containing medicament. When preparing a drug containing radioactive isotope, typically, but not limited to, 18 F is used as the F atom contained in the compound, and 131 is used as the I atom contained in the compound. I, 123 I can be used, or 11 C can be used as the C atom contained in the compound. As for the position of these radioisotopes, they can be introduced at any position of R3 , or as a substituent when R4 or R5 contains aryl or heteroaryl. Compounds thus obtained can be used, for example, in RI examinations and nuclear medicine examinations. These include, but are not limited to, agents for scintigraphic tomography, SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography), i.e., injecting radioactivity into a subject. The boronophenylalanine amide derivative of the present invention containing is administered as a PET drug or SPECT drug, an image is acquired before treatment, and the distribution of the derivative in the body, the tumor tissue / normal tissue abundance ratio (T / N ratio), etc. Information can be obtained.Based on this information, it is also possible to presume the therapeutic effect of BNCT and formulate a research or treatment plan.In addition, the mode of administration and others are described in [BNCT (Boron Neutron Capture Therapy) ) drugs].
以下の実施例により、本発明をさらに詳述するが、かかる発明はこれに限定されるものではない。 The present invention will be described in more detail by the following examples, but the invention is not limited thereto.
なお、下記実施例において、化合物の分析及び分離精製には以下の機種や試薬を用いて行った。 In the following examples, the following models and reagents were used for the analysis and separation and purification of the compounds.
・NMRスペクトル:
(JEOL RESONANCE/JNM-ECZ500R/500MHz
・NMR spectrum:
(JEOL RESONANCE/JNM-ECZ500R/500MHz
(実施例1)
(S)‐(4‐(2‐アミノ‐3‐(ベンゾ[d][1,3]ジオキソール‐5‐イルアミノ)‐3‐オキソプロピル)フェニル)ボロン酸の製造
Preparation of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid
ステップ1
tert-ブチル(S)‐(1‐(ベンゾ[d][1,3]ジオキソール‐5‐イルアミノ)‐3‐(4‐ヨードフェニル)‐1‐オキソプロパン‐2‐イル)カルバメートの製造
Boc-4-ヨード-L-フェニルアラニン(4.00g,10.2mmol)、1,2,3-ベンゾトリアゾール-1-オール一水和物(1.87g,12.2mmol)、3,4-メチレンジオキシアニリン(1.67g,12.2mmol)をDMF(80mL)に溶解させた。これを氷浴下、予めDMF(27mL)に溶解させておいた1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(2.74g,14.3mmol)を添加した。その後、室温に戻し、終夜攪拌した。反応終了後、酢酸エチル(27mL)および蒸留水(27mL)を加えた。約5分間撹拌させた後、分液漏斗に移した。水層をさらに酢酸エチル(29mL)にて抽出し、得られた酢酸エチル層を合わせ、飽和食塩水(27mL)で洗浄した。無水硫酸マグネシウムにて乾燥後、濾過により得られた残渣をシリカゲルカラムクロマトグラフィーにて粗精製し、目的物4.2 gを得た(収率81%)。
1H NMR (DMSO-d6); 1.26 (s, 9H, t-Bu), 2.75 (dd, J = 10.5, 14.0 Hz, 1H, β-H), 2.92 (dd, J = 4.0, 13.5 Hz, 1H, β-H), 3.71 (s, OCH
2 O), 4.23-4.28 (m, 1H, α-H), 6.63 (d, J = 8.0 Hz, 1H, NH), 7.11-7.13 (m, 3H, ArH), 7.20 (t, J = 8.0 Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 10.05 (s, 1H, NH).
step one
Preparation of tert-butyl (S)-(1-(benzo[d][1,3]dioxol-5-ylamino)-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamate Boc- 4-iodo-L-phenylalanine (4.00 g, 10.2 mmol), 1,2,3-benzotriazol-1-ol monohydrate (1.87 g, 12.2 mmol), 3,4-methylenedioxy Aniline (1.67 g, 12.2 mmol) was dissolved in DMF (80 mL). Under an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.74 g, 14.3 mmol) dissolved in DMF (27 mL) in advance was added. Then, it was returned to room temperature and stirred overnight. After completion of the reaction, ethyl acetate (27 mL) and distilled water (27 mL) were added. After stirring for about 5 minutes, it was transferred to a separatory funnel. The aqueous layer was further extracted with ethyl acetate (29 mL), and the obtained ethyl acetate layers were combined and washed with saturated brine (27 mL). After drying with anhydrous magnesium sulfate, the residue obtained by filtration was crudely purified by silica gel column chromatography to obtain 4.2 g of the desired product (yield 81%).
1 H NMR (DMSO-d 6 ); 1.26 (s, 9H, t-Bu), 2.75 (dd, J = 10.5, 14.0 Hz, 1H, β-H), 2.92 (dd, J = 4.0, 13.5 Hz, 1H, β-H), 3.71 (s, OC H 2 O), 4.23-4.28 (m, 1H, α-H), 6.63 (d, J = 8.0 Hz, 1H, NH), 7.11-7.13 (m, 3H, ArH), 7.20 (t, J = 8.0 Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 10.05 (s, 1H, NH) .
ステップ2
(S)‐(4‐(3‐(ベンゾ[d][1,3]ジオキソール‐5‐イルアミノ)‐2‐((tert-ブトキシカルボニル)アミノ)‐3‐オキソプロピル)フェニル)ボロン酸の製造
DMSO(42mL)に、ステップ1で得られたBoc化合物(4.20g,8.23mmol)Pd(dppf)2・CH2Cl2(336mg,0.412mmol)、酢酸カリウム(1.60g,16.5mmol)を加え、100℃、2時間反応させた。反応終了後、反応液を氷浴中にて冷却させ、酢酸エチル(42mL)および蒸留水(42mL)を加えた。約5分間撹拌させた後、セライト濾過し、得られた濾液を分液漏斗に移した。水層をさらに酢酸エチル(42mL)にて抽出し、得られた酢酸エチル層を合わせ、飽和食塩水(42mL)で洗浄した。無水硫酸マグネシウムにて乾燥後、濾過により得られた残渣をシリカゲルカラムクロマトグラフィーにて粗精製した。
得られた粗生成物をアセトン(200mL)に溶解させた。別途、過ヨウ素酸ナトリウム(4.40g,20.6mmol)、酢酸アンモニウム(2.00g,20.6mmol)を蒸留水(200mL)に溶解させておいた水溶液を、このアセトン溶液に加えた。その後、室温にて、2日間反応させた。反応終了後アセトンを減圧留去し、得られた水溶液を酢酸エチル(84mL)にて2回抽出した。その後、無水硫酸マグネシウムにて乾燥後、これを濾別し、酢酸エチル溶液を減圧留去させた。これをシリカゲルカラムクロマトグラフィーにて精製し、目的物1.9gを得た(収率55%)。
1H NMR (DMSO-d6); 1.30 (s, 9H, t-Bu), 2.81 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 2.96 (dd, J = 5.0, 14.0 Hz, 1H, β-H), 3.71 (s, OCH
2 O), 4.27-4.32 (m, 1H, α-H), 6.62 (d, J = 7.5 Hz, 1H, NH), 7.08-7.13 (m, 2H, ArH), 7.20 (t, J = 8.0 Hz, 1H, ArH), 7.25-7.27 (m, 3H, ArH), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.98 (s, 2H, B(OH)2), 10.04 (s, 1H, NH).
step 2
Preparation of (S)-(4-(3-(benzo[d][1,3]dioxol-5-ylamino)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)boronic acid In DMSO (42 mL) was added the Boc compound obtained in step 1 (4.20 g, 8.23 mmol) Pd (dppf) 2.CH2Cl2 ( 336 mg, 0.412 mmol), potassium acetate (1.60 g, 16.0 mmol). 5 mmol) was added and reacted at 100° C. for 2 hours. After completion of the reaction, the reaction solution was cooled in an ice bath, and ethyl acetate (42 mL) and distilled water (42 mL) were added. After stirring for about 5 minutes, the mixture was filtered through celite, and the resulting filtrate was transferred to a separatory funnel. The aqueous layer was further extracted with ethyl acetate (42 mL), and the obtained ethyl acetate layers were combined and washed with saturated brine (42 mL). After drying over anhydrous magnesium sulfate, the residue obtained by filtration was crudely purified by silica gel column chromatography.
The crude product obtained was dissolved in acetone (200 mL). Separately, an aqueous solution prepared by dissolving sodium periodate (4.40 g, 20.6 mmol) and ammonium acetate (2.00 g, 20.6 mmol) in distilled water (200 mL) was added to this acetone solution. Then, it was made to react for 2 days at room temperature. After completion of the reaction, acetone was distilled off under reduced pressure, and the resulting aqueous solution was extracted twice with ethyl acetate (84 mL). Then, after drying with anhydrous magnesium sulfate, this was separated by filtration, and the ethyl acetate solution was distilled off under reduced pressure. This was purified by silica gel column chromatography to obtain 1.9 g of the desired product (yield 55%).
1 H NMR (DMSO-d 6 ); 1.30 (s, 9H, t-Bu), 2.81 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 2.96 (dd, J = 5.0, 14.0 Hz, 1H, β-H), 3.71 (s, OC H 2 O), 4.27-4.32 (m, 1H, α-H), 6.62 (d, J = 7.5 Hz, 1H, NH), 7.08-7.13 (m, 2H, ArH), 7.20 (t, J = 8.0 Hz, 1H, ArH), 7.25-7.27 (m, 3H, ArH), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.98 (s, 2H, B(OH) 2 ), 10.04 (s, 1H, NH).
ステップ3
(S)-(4-(2-アミノ-3-(ベンゾ[d][1,3]ジオキソール-5-イルアミノ)-3-オキソプロピル)フェニル)ボロン酸の製造
ステップ2で得られた脱ピナコール体(1.00g,2.34mmol)をトリフルオロ酢酸(10 mL)に溶解させた。約3時間静置させた後、減圧濃縮させた。少量の蒸留水で溶解させ、炭酸ナトリウムで中和し、目的物を析出させた。これを濾取し、冷水で洗浄すると目的物0.35gが得られた(収率46%)。
1H NMR (3.5% DCl in D2O); 3.22 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.37 (dd, J = 6.5, 13.0 Hz, 1H, β-H), 4.27 (dd, J = 6.5, 9.0 Hz, 1H, α-H), 5.96 (s, 1H, OCH2O), 6.60 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.76 (d, J = 2.5 Hz, 1H, ArH). 6.81 (d, J = 8.0 Hz, 1H, ArH), 7.34 (d, J = 7.5 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 1H, ArH).
step 3
Preparation of (S)-(4-(2-amino-3-(benzo[d][1,3]dioxol-5-ylamino)-3-oxopropyl)phenyl)boronic acid Depinacol obtained in Step 2 The compound (1.00 g, 2.34 mmol) was dissolved in trifluoroacetic acid (10 mL). After allowing to stand for about 3 hours, it was concentrated under reduced pressure. It was dissolved with a small amount of distilled water and neutralized with sodium carbonate to precipitate the desired product. This was collected by filtration and washed with cold water to obtain 0.35 g of the desired product (yield 46%).
1 H NMR (3.5% DCl in D 2 O); 3.22 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.37 (dd, J = 6.5, 13.0 Hz, 1H, β-H), 4.27 (dd, J = 6.5, 9.0 Hz, 1H, α-H), 5.96 (s, 1H, OCH 2 O), 6.60 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.76 (d, J = 2.5 Hz, 1H, ArH). 6.81 (d, J = 8.0 Hz, 1H, ArH), 7.34 (d, J = 7.5 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 1H, ArH).
(実施例2)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.54 (d, J = 7.5 Hz, 0.8H, ArH (minor)), 7.53 (d, J = 7.5 Hz, 1.2H, ArH (major)), 7.19 (d, J = 7.5 Hz, 0.8H, ArH), 7.17 (d, J = 7.5 Hz, 1.2H, ArH (major)), 4.24 (dd, J = 6.0, 8.5 Hz, 0.4H, CH (minor)), 3.66 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.04 (dd, J = 6.0, 14.0 Hz, 0.4H, CH2), 2.97-2.91 (m, 1H, CH2), 2.86 (dd, J = 6.5, 14.0 Hz, 0.6H, CH2 (major)).
(Example 2)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O containing K2CO3 ): δ 7.54 (d, J = 7.5 Hz, 0.8H , ArH (minor)), 7.53 (d, J = 7.5 Hz, 1.2H, ArH (major)) , 7.19 (d, J = 7.5 Hz, 0.8H, ArH), 7.17 (d, J = 7.5 Hz, 1.2H, ArH (major)), 4.24 (dd, J = 6.0, 8.5 Hz, 0.4H, CH ( minor)), 3.66 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.04 (dd, J = 6.0, 14.0 Hz, 0.4H, CH2 ), 2.97-2.91 (m, 1H, CH2 ), 2.86 (dd, J = 6.5, 14.0 Hz, 0.6H, CH 2 (major)).
(実施例3)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.53-7.51 (m, 2H, ArH), 7.15-7.10 (m, 2H, ArH), 4.21 (t, J = 7.0 Hz, 0.4H, CH (minor)), 3.59 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.02-2.84 (m, 2H, CH2), 2.69 (s, 1.2H, CH3(minor)), 2.65 (s, 1.8H, CH3 (major)).
(Example 3)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O containing K 2 CO 3 ): δ 7.53-7.51 (m, 2H, ArH), 7.15-7.10 (m, 2H, ArH), 4.21 (t, J = 7.0 Hz, 0.4H, CH (minor)), 3.59 (t, J = 6.5 Hz, 0.6H, CH (major)), 3.02-2.84 (m, 2H, CH 2 ), 2.69 (s, 1.2H, CH 3 (minor)), 2.65 (s, 1.8H, CH3 (major)).
(実施例4)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.63-7.60 (m, 2H, ArH), 7.23 (d. J = 8.0 Hz, 0.4H, ArH (minor)), 7.19 (d, J = 6.5 Hz, 1.6H, ArH (major)), 4.77 (t, J = 8.0 Hz, 0.2H, CH (minor)), 4.21 (t, J = 7.0 Hz, 0.8H, CH (major)), 2.99-2.72 (m, 8H, CH2, CH3).
(Example 4)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O containing K2CO3 ): δ 7.63-7.60 (m, 2H, ArH), 7.23 (d. J = 8.0 Hz, 0.4H, ArH (minor ) ), 7.19 (d, J = 6.5 Hz, 1.6H, ArH (major)), 4.77 (t, J = 8.0 Hz, 0.2H, CH (minor)), 4.21 (t, J = 7.0 Hz, 0.8H, CH (major)), 2.99- 2.72 (m, 8H, CH2 , CH3 ).
(実施例5)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 0.93 (t, J = 7.5 Hz, 3H, OCH2
CH
3 ), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, β-H), 3.17 (q, J = 7.5 Hz, 2H, OCH
2 CH3), 3.29 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.22 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH).
(Example 5)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 0.93 (t, J = 7.5 Hz, 3H, OCH 2 CH 3 ), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, β-H), 3.17 ( q, J = 7.5 Hz, 2H, O CH 2 CH 3 ), 3.29 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.22 (dd, J = 6.5, 8.0 Hz, 1H, α-H ), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH).
(実施例6)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.52 (d, J = 5.0 Hz, 2H, ArH), 7.15 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 4.71 (t, J = 10.0 Hz, 0.5H, CH), 4.03 (t, J = 10.0 Hz, 0.5H, CH), 3.46 (m, 1H, ArH), 3.26-2.99 (m, 3H, CH2), 2.91-2.82 (m, 2H, CH2), 1.07-0.99 (m, 6H, CH3).
(Example 6)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O containing K 2 CO 3 ): δ 7.52 (d, J = 5.0 Hz, 2H, ArH), 7.15 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 4.71 (t, J = 10.0 Hz, 0.5H, CH), 4.03 (t, J = 10.0 Hz, 0.5H, CH), 3.46 (m, 1H, ArH), 3.26-2.99 (m, 3H, CH 2 ), 2.91-2.82 ( m, 2H, CH2 ), 1.07-0.99 (m, 6H, CH3 ).
(実施例7)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.52 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.52 (d, J = 8.0 Hz, 1.4H, ArH (major)), 7.16 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.13 (d, J = 8.0 Hz, 1.4H, ArH (major)), 4.13 (t, J = 6.5 Hz, 0.3H, CH (minor)), 3.49 (t, J = 7.0 Hz, 0.7H, CH (major)), 2.93-2.80 (m, 2H, CH2), 1.24 (s, 2.7H, CH3 (minor)), 1.21 (s, 6.3H, CH3).
(Example 7)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O containing K2CO3 ): δ 7.52 (d, J = 7.5 Hz, 0.6H, ArH (minor ) ), 7.52 (d, J = 8.0 Hz, 1.4H, ArH (major)) , 7.16 (d, J = 7.5 Hz, 0.6H, ArH (minor)), 7.13 (d, J = 8.0 Hz, 1.4H, ArH (major)), 4.13 (t, J = 6.5 Hz, 0.3H, CH (minor)), 3.49 (t, J = 7.0 Hz, 0.7H, CH (major)), 2.93-2.80 (m, 2H, CH 2 ), 1.24 (s, 2.7H, CH 3 (minor)), 1.21 (s, 6.3H, CH3 ).
(実施例8)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 4.07 (dd, J = 6.0, 9.5 Hz, 1H, CH), 3.47 (m, 1H, CH), 3.27 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.09 (dd, J = 9.5, 13.5 Hz, 1H, CH2), 1.72 (m, 1H, CH2), 1.62 (m, 1H, CH2), 1.53-1.49 (m, 2H, CH2), 1.41 (m, 1H, CH2), 1.29-1.02 (m, 4H, CH2), 0.81 (m, 1H, CH2).
(Example 8)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 4.07 (dd, J = 6.0, 9.5 Hz, 1H , CH), 3.47 (m, 1H, CH), 3.27 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.09 (dd, J = 9.5, 13.5 Hz, 1H, CH 2 ), 1.72 (m , 1H, CH 2 ), 1.62 (m, 1H, CH 2 ), 1.53-1.49 (m, 2H, CH 2 ), 1.41 (m, 1H, CH 2 ), 1.29-1.02 (m, 4H, CH 2 ) , 0.81 (m, 1H, CH2 ).
(実施例9)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.51-7.49 (m, 2H, ArH), 7.16-7.12 (m, 2H, ArH), 4.53 (dd, J = 6.5, 8.25 Hz, 0.5H, CH (A-isomer)), 3.91 (dd, J = 6.0, 8.5 Hz, 0.5H, CH (B-isomer)), 3.53-3.23 (m, 3H, CH2), 2.95-2.80 (m, 3H, CH2), 1.81-1.59 (m, 4H, CH2).
(Example 9)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O containing K 2 CO 3 ): δ 7.51-7.49 (m, 2H, ArH), 7.16-7.12 (m, 2H, ArH), 4.53 (dd, J = 6.5, 8.25 Hz, 0.5H , CH (A-isomer)), 3.91 (dd, J = 6.0, 8.5 Hz, 0.5H, CH (B-isomer)), 3.53-3.23 (m, 3H, CH2), 2.95-2.80 (m, 3H, CH2 ), 1.81-1.59 (m, 4H, CH2 ).
(実施例10)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.78 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 4.76 (dd, J = 6.0, 9.5 Hz, 1H, CH), 3.71-3.62 (m, 2H, CH2), 3.50-3.39 (m, 3H, CH2), 3.34-3.27 (m, 2H, CH2), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, CH2), 3.01 (m, 1H, CH2), 2.69 (m, 1H, CH2).
(Example 10)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.78 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 4.76 (dd, J = 6.0, 9.5 Hz, 1H , CH), 3.71-3.62 (m, 2H, CH 2 ), 3.50-3.39 (m, 3H, CH 2 ), 3.34-3.27 (m, 2H, CH 2 ), 3.12 (dd, J = 9.5, 13.5 Hz , 1H, CH 2 ), 3.01 (m, 1H, CH 2 ), 2.69 (m, 1H, CH 2 ).
(実施例11)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.74 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 7.41-7.34 (m, 4H, ArH), 7.28-7.24 (m, 3H, ArH), 4.39 (t, J = 15.0 Hz, 1H, CH), 3.38 (dd, J = 5.0, 15.0 Hz, 1H, CH2), 3.26 (dd, J = 5.0, 15.0 Hz, 1H, CH2).
(Example 11)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O containing K 2 CO 3 ): δ 7.74 (dd, J = 5.0, 10.0 Hz, 2H, ArH), 7.41-7.34 (m, 4H, ArH), 7.28-7.24 (m, 3H, ArH), 4.39 (t, J = 15.0 Hz, 1H, CH), 3.38 (dd, J = 5.0, 15.0 Hz, 1H, CH2 ), 3.26 (dd, J = 5.0, 15.0 Hz, 1H, CH2 ) .
(実施例12)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 10.27 (brd, J = 9.5 Hz, 1H), 8.47 (brs, 3H), 8.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H, ArH), 7.82-7.3 (m, 10H, ArH), 4.40 (t, J = 8.0 Hz, 1H, CH), 3.27-3.16 (m, 2H, CH2).
(Example 12)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 10.27 (brd, J = 9.5 Hz, 1H), 8.47 (brs, 3H), 8.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H, ArH) , 7.82-7.3 (m, 10H, ArH), 4.40 (t, J = 8.0 Hz, 1H, CH), 3.27-3.16 (m, 2H, CH 2 ).
(実施例13)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O containing K2CO3): δ 7.63-6.86 (m, 9H, ArH), 4.34 (t, J = 10.0 Hz, 0.6H, CH (major)), 3.62 (t, J = 10.0 Hz, 0.4H, CH (minor)), 3.20 (s, 1.8H CH3 (major)), 3.18 (s, 1.4H, CH3(minor)), 2.84 (m, 1H, CH2), 2.65 (m, 1H, CH2).
(Example 13)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O containing K2CO3 ): δ 7.63-6.86 (m, 9H, ArH), 4.34 (t, J = 10.0 Hz, 0.6H, CH ( major )), 3.62 (t, J = 10.0 Hz, 0.4H, CH (minor)), 3.20 (s, 1.8H CH3 (major)), 3.18 (s, 1.4H, CH3 (minor)), 2.84 (m, 1H, CH2 ), 2.65 (m, 1H, CH2 ).
(実施例14)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.36-7.32 (m, 3H, ArH), 7.06-7.02 (m, 4H, ArH), 6.78-6.75 (m, 2H, ArH), 4.44 (d, J = 15.0 Hz, 1H, CH2), 4.18 (dd, J = 6.0, 10.0 Hz, 1H, CH), 4.13 (d, J = 15.0 Hz, 1H, CH2), 3.19 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH2).
(Example 14)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.36-7.32 (m, 3H, ArH), 7.06-7.02 (m, 4H, ArH), 6.78-6.75 (m, 2H, ArH), 4.44 (d, J = 15.0 Hz, 1H, CH2 ), 4.18 (dd, J = 6.0, 10.0 Hz, 1H, CH), 4.13 (d, J = 15.0 Hz, 1H, CH2 ), 3.19 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH 2 ).
(実施例15)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 8.34 (brs, 1H), 7.71-7.68 (m, 2H, ArH), 7.27-6.97 (m, 7H, ArH), 4.53-4.24 (m, 3H, CH2, CH), 2.91-2.89 (m, 2H, CH2), 2.70 (s, 3H, CH3 (minor)), 2.67 (s, 3H, CH3(major)).
(Example 15)
The following compounds were prepared in the same manner as in Example 1.
1H NMR (DMSO- d6 ): δ 8.34 (brs, 1H), 7.71-7.68 (m, 2H, ArH), 7.27-6.97 (m, 7H, ArH), 4.53-4.24 (m, 3H, CH2 , CH), 2.91-2.89 (m, 2H, CH 2 ), 2.70 (s, 3H, CH 3 (minor)), 2.67 (s, 3H, CH 3 (major)).
(実施例16)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 7.99 (brs, 2H), 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.28-7.01 (m, 12H, ArH), 4.53-4.29 (m, 4H, CH2), 3.90 (t, J = 7.0 Hz, 1H, CH), 2.90 (dd, J = 7.0, 13.0 Hz, 1H, CH2), 2.72 (dd, J = 7.0, 13.0 Hz, 1H, CH2).
(Example 16)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 7.99 (brs, 2H), 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.28-7.01 (m, 12H, ArH), 4.53-4.29 (m, 4H , CH 2 ), 3.90 (t, J = 7.0 Hz, 1H, CH ), 2.90 (dd, J = 7.0, 13.0 Hz, 1H, CH 2 ), 2.72 (dd, J = 7.0, 13.0 Hz, 1H, CH 2 ).
(実施例17)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.54 (d, J = 7.5 Hz, 2H, ArH), 7.31-7.25 (m, 3H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 6.92-6.90 (m, 2H, ArH), 4.82 (m, 1H, CH), 4.15 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH2), 1.35 (d, J = 7.5 Hz, 3H, CH3).
(Example 17)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.54 (d, J = 7.5 Hz, 2H, ArH), 7.31-7.25 (m, 3H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 6.92. -6.90 (m, 2H, ArH), 4.82 (m, 1H, CH), 4.15 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.01 (dd, J = 10.0, 13.5 Hz, 1H, CH 2 ), 1.35 (d, J = 7.5 Hz, 3H, CH 3 ).
(実施例18)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.79 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.26 (m, 7H, ArH), 4.72 (m, 1H, CH), 4.19 (m, 1H, CH), 3.32 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.14 (dd, J = 9.0, 13.5 Hz, 1H, CH2), 1.12 (d, J = 7.0 Hz, 3H, CH3).
(Example 18)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O): δ 7.79 (d, J = 8.0 Hz, 2H, ArH), 7.40-7.26 (m, 7H, ArH), 4.72 (m, 1H, CH), 4.19 (m, 1H, CH), 3.32 (dd, J = 6.0, 13.5 Hz, 1H, CH2 ), 3.14 (dd, J = 9.0, 13.5 Hz, 1H, CH2 ), 1.12 (d, J = 7.0 Hz, 3H, CH3 ).
(実施例19)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.82 (d, J = 7.5 Hz, 2H, ArH), 7.36-7.26 (m, 5H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 4.31 (dd, J = 6.0, 9.0 Hz, 1H, CH), 3.27 (dd, J = 6.0, 14.0 Hz, 1H, CH2), 3.12 (dd, J = 9.0, 14.0 Hz, 1H, CH2), 1.51 (s, 3H, CH3), 1.43 (s, 3H, CH3).
(Example 19)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.82 (d, J = 7.5 Hz, 2H, ArH), 7.36-7.26 (m, 5H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 4.31. (dd, J = 6.0, 9.0 Hz, 1H, CH), 3.27 (dd, J = 6.0, 14.0 Hz , 1H, CH2), 3.12 (dd, J = 9.0, 14.0 Hz, 1H, CH2 ), 1.51 (s, 3H, CH3 ), 1.43 (s, 3H, CH3 ).
(実施例20)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 2.23 (s, 3H, CH3), 3.28 (dd, J = 8.5, 13.5 Hz, 1H, β-H), 3.40 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 4.44 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(Example 20)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 2.23 (s, 3H, CH 3 ), 3.28 (dd, J = 8.5, 13.5 Hz, 1H, β-H), 3.40 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 4.44 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(実施例21)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 10.37 (brs, 1H), 8.35 (brs, 3H), 8.13 (brs, 1H), 7.73 (d, J = 8.0 Hz, 1.3H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.7H, ArH (minor)), 7.34-7.20 (m, 5H, ArH), 6.93 (d, J = 7.5 Hz, 1H, ArH), 4.16 (t, J = 7.0 Hz, 1H, CH), 3.17 (m, 1H, CH2), 3.08 (m, 1H, CH2), 2.28 (s, 3H, CH3).
(Example 21)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 10.37 (brs, 1H), 8.35 (brs, 3H), 8.13 (brs, 1H), 7.73 (d, J = 8.0 Hz, 1.3H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.7H, ArH (minor)), 7.34-7.20 (m, 5H, ArH), 6.93 (d, J = 7.5 Hz, 1H, ArH), 4.16 (t, J = 7.0 Hz, 1H, CH), 3.17 (m, 1H, CH2 ), 3.08 (m, 1H, CH2 ), 2.28 (s, 3H, CH3 ).
(実施例22)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 2.18 (s, 6H, CH
3 ×2), 3.22 (dd, J = 9.0, 13.5 Hz, 1H, β-H), 3.39 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.32 (dd, J = 7.0, 9.0 Hz, 1H, α-H), 6.86 (d, J = 2.0 Hz, 1H, ArH), 6.96 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz, 2H, ArH).
(Example 22)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 2.18 (s, 6H, CH 3 ×2), 3.22 (dd, J = 9.0, 13.5 Hz, 1H, β-H), 3.39 (dd, J = 6.5 , 13.5 Hz, 1H, β-H), 4.32 (dd, J = 7.0, 9.0 Hz, 1H, α-H), 6.86 (d, J = 2.0 Hz, 1H, ArH), 6.96 (dd, J = 2.5 , 8.5 Hz, 1H, ArH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz, 2H, ArH) .
(実施例23)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 10.45 (brs, 0.25H (minor)), 10.42 (brs, 0.75H (major)), 8.38 (brs, 2H), 7.74 (d, J = 7.5 Hz, 1.5H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.43 (d, J = 6.5 Hz, 2H, ArH), 7.35 (d, J = 6.5 Hz, 2H, ArH), 7.29 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.23 (d, J = 7.5 Hz, 1.5H, ArH (major)), 4.17 (m, 1H, CH), 3.21-3.07 (m, 2H, CH2), 1.27 (s, 2.25H, CH3 (minor)), 1.25 (s, 6.75H, CH3 (major)).
(Example 23)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 10.45 (brs, 0.25H (minor)), 10.42 (brs, 0.75H (major)), 8.38 (brs, 2H), 7.74 (d, J = 7.5 Hz, 1.5 H, ArH (major)), 7.62 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.43 (d, J = 6.5 Hz, 2H, ArH), 7.35 (d, J = 6.5 Hz, 2H , ArH), 7.29 (d, J = 7.5 Hz, 0.5H, ArH (minor)), 7.23 (d, J = 7.5 Hz, 1.5H, ArH (major)), 4.17 (m, 1H, CH), 3.21 -3.07 (m, 2H, CH 2 ), 1.27 (s, 2.25H, CH 3 (minor)), 1.25 (s, 6.75H, CH 3 (major)).
(実施例24)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 9.68 (s, 1H), 8.37 (s, 3H), 8.14 (s, 2H), 7.82 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 7.75 (d, J = 7.5 Hz, 2H, ArH), 7.26 (d, J = 7.5 Hz, 2H, ArH), 7.13 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 7.05 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 6.93 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 4.44 (t, J = 7.0 Hz, 1H, CH), 3.78 (s, 3H, CH3), 3.14 (dd, J = 7.0, 13.5 Hz, 1H, CH2), 3.08 (dd, J = 7.0, 13.5 Hz, 1H, CH2).
(Example 24)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 9.68 (s, 1H), 8.37 (s, 3H), 8.14 (s, 2H), 7.82 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 7.75 ( d, J = 7.5 Hz, 2H, ArH), 7.26 (d, J = 7.5 Hz, 2H, ArH), 7.13 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 7.05 (dd, J = 1.5, 8.0 Hz, 1H, ArH), 6.93 (dt, J = 1.5, 8.0 Hz, 1H, ArH), 4.44 (t, J = 7.0 Hz, 1H, CH), 3.78 (s, 3H, CH3 ), 3.14 ( dd, J = 7.0, 13.5 Hz, 1H, CH2 ), 3.08 (dd, J = 7.0, 13.5 Hz, 1H, CH2 ).
(実施例25)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH3), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(Example 25)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH3 ), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(実施例26)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH3), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(Example 26)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.40 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 3.77 (s, 3H, OCH3 ), 4.46 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.78-81 (m, 2H, ArH), 6.89-6.90 (m, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(実施例27)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 3.23 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.41 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.42 (dd, J = 6.0, 8.5 Hz, 1H, α-H), 6.63 (d, J = 2.5 Hz, 1H, ArH), 6.79 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.87 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 8.0 Hz, 2H, ArH).
(Example 27)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 3.23 (dd, J = 8.5, 13.0 Hz, 1H, β-H), 3.41 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.75 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3 ), 4.42 (dd, J = 6.0, 8.5 Hz, 1H, α-H), 6.63 (d, J = 2.5 Hz, 1H, ArH) , 6.79 (dd, J = 2.5, 8.5 Hz, 1H, ArH), 6.87 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 8.0Hz, 2H, ArH).
(実施例28)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 6.42 (s, 2H, ArH), 4.31 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.80 (s, 6H, CH3), 3.74 (s, 3H, CH3), 3.44 (dd, J = 6.5, 13.5 Hz, 1H, CH2), 3.18 (dd, J = 9.5, 13.5 Hz, 1H, CH2).
(Example 28)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 6.42 (s, 2H, ArH), 4.31 (dd , J = 6.5, 9.5 Hz, 1H, CH), 3.80 (s, 6H, CH3 ), 3.74 (s, 3H, CH3 ), 3.44 (dd, J = 6.5, 13.5 Hz, 1H, CH2 ), 3.18 (dd, J = 9.5, 13.5Hz, 1H, CH2 ).
(実施例29)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.38 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 4.24 (s, 4H, OCH2CH2O), 4.44 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.69 (dd, J = 2.0 Hz, 8.5, 1H, Ar), 6.78 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH).
(Example 29)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 3.27 (dd, J = 8.5, 14.0 Hz, 1H, β-H), 3.38 (dd, J = 7.0, 14.0 Hz, 1H, β-H), 4.24 (s, 4H, OCH2CH2O ), 4.44 (dd, J = 7.0, 8.5 Hz, 1H, α-H), 6.69 (dd , J = 2.0 Hz, 8.5, 1H, Ar), 6.78 (d, J = 2.0 Hz, 1H, ArH), 6.81 (d, J = 8.5 Hz, 1H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH ).
(実施例30)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 3.12 (dd, J = 7.5, 13.5 Hz, 1H, β-H), 3.19 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.26 (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 9.0 Hz, 2H, ArH), 7.54 (d, J = 8.0 Hz, 2H, ArH), 7.92 (d, J = 9.5 Hz, 2H, ArH).
(Example 30)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (3.5% DCl in D 2 O); 3.12 (dd, J = 7.5, 13.5 Hz, 1H, β-H), 3.19 (dd, J = 6.5, 13.5 Hz, 1H, β-H), 4.26. (dd, J = 6.5, 8.0 Hz, 1H, α-H), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.32 (d, J = 9.0 Hz, 2H, ArH), 7.54 (d, J = 8.0 Hz, 2H, ArH), 7.92 (d, J = 9.5 Hz, 2H, ArH).
(実施例31)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.73 (d, J = 7.5 Hz, 2H, ArH), 7.34 (t, J = 7.5 Hz, 2H, ArH), 7.28 (dd, J = 6.0, 7.5 Hz, 1H, ArH), 7.21 (d, J = 7.5 Hz, 2H, ArH), 7.14 (d, J = 7.5 Hz, 2H, ArH), 4.13 (t, J = 8.0 Hz, 1H, CH), 3.55 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH2), 3.31 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH2), 3.15 (dd, J = 8.0, 13.5 Hz, 1H, CH2), 3.08 (dd, J = 8.0, 13.5 Hz, 1H, CH2), 2.71-2.61 (m, 2H, ArH).
(Example 31)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.73 (d, J = 7.5 Hz, 2H, ArH), 7.34 (t, J = 7.5 Hz, 2H, ArH), 7.28 (dd, J = 6.0, 7.5 Hz, 1H , ArH), 7.21 (d, J = 7.5 Hz, 2H, ArH), 7.14 (d, J = 7.5 Hz, 2H, ArH), 4.13 (t, J = 8.0 Hz, 1H, CH), 3.55 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH2 ), 3.31 (ddd, J = 7.0, 8.0, 13.5 Hz, 1H, CH2 ), 3.15 (dd, J = 8.0, 13.5 Hz, 1H, CH2 ) , 3.08 (dd, J = 8.0, 13.5 Hz, 1H, CH 2 ), 2.71-2.61 (m, 2H, ArH).
(実施例32)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.70 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 7.16 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 7.04 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 6.89 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 4.12 (dd, J = 6.5, 8.0 Hz, 1H, CH), 3.79 (s, 3H, CH3), 3.53 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH2), 3.25 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH2), 3.13 (dd, J = 6.5, 14.0 Hz, 1H, CH2), 3.06 (dd, J = 8.0, 14.0 Hz, 1H, CH2), 2.60 (m, 2H, CH2).
(Example 32)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.70 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 7.16 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 7.04 (dd, J = 2.5, 8.5 Hz, 2H, ArH), 6.89 (dd, J = 2.5, 8.0 Hz, 2H, ArH), 4.12 (dd, J = 6.5, 8.0 Hz, 1H, CH), 3.79 (s, 3H, CH3 ), 3.53 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH2 ), 3.25 (ddd, J = 6.5, 7.0, 13.5 Hz, 1H, CH2 ), 3.13 (ddd, J = 6.5, 14.0 Hz, 1H , CH 2 ), 3.06 (dd, J = 8.0, 14.0 Hz, 1H, CH 2 ), 2.60 (m, 2H, CH 2 ).
(実施例33)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.85 (m, 1H, ArH), 6.76-6.74 (m, 2H, ArH), 4.12 (dd, J = 6.5, 8.5 Hz, 1H, CH), 3.79 (s, 3H, CH3), 3.56 (m, 1H, CH2), 3.29 (m, 1H, CH2), 3.12 (dd, J = 6.5, 13.5 Hz, 1H, CH2), 3.05 (dd, J = 8.5, 13.5 Hz, 1H, CH2), 2.66-2.63 (m, 2H, CH2).
(Example 33)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.68 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH ), 6.85 (m, 1H, ArH), 6.76-6.74 (m, 2H, ArH), 4.12 (dd, J = 6.5, 8.5 Hz, 1H, CH), 3.79 (s, 3H, CH 3 ), 3.56 ( m, 1H, CH 2 ), 3.29 (m, 1H, CH 2 ), 3.12 (dd, J = 6.5, 13.5 Hz, 1H, CH 2 ), 3.05 (dd, J = 8.5, 13.5 Hz, 1H, CH 2 ), 2.66-2.63 (m, 2H, CH2 ).
(実施例34)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 8.48 (t, J = 5.5 Hz, 1H), 8.22 (brs, 3H), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.16-7.06 (m, 6H, ArH), 3.93 (m, 1H, CH), 3.39 (m, 1H, CH2), 3.18 (m, 1H, CH2), 2.99 (dd, J = 6.5, 13.5 Hz, 1H, CH2), 2.92 (dd, J = 7.0, 13.5 Hz, 1H, CH2), 2.60 (m, 2H, CH2).
(Example 34)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 8.48 (t, J = 5.5 Hz, 1H), 8.22 (brs, 3H), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.16-7.06 (m, 6H, ArH), 3.93 (m, 1H, CH), 3.39 (m, 1H, CH2 ), 3.18 (m, 1H, CH2 ), 2.99 (dd, J = 6.5, 13.5 Hz, 1H, CH2 ) , 2.92 (dd, J = 7.0, 13.5 Hz, 1H, CH 2 ), 2.60 (m, 2H, CH 2 ).
(実施例35)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 8.05-8.03 (m, 2H), 7.72 (d, J = 7.5 Hz, 2H, ArH), 7.28-7.11 (m, 9H, ArH, NH2), 3.58 (t, J = 7.0 Hz, 1H, CH), 3.10-2.97 (m, 2H, CH2), 2.94 (dd, J = 7.0, 13.5 Hz, 1H, CH2), 2.76 (dd, J = 7.0, 13.5 Hz, 1H, CH2), 2.49-2.46 (m, 2H, CH2), 1.65-1.59 (m, 2H, CH2).
(Example 35)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 8.05-8.03 (m, 2H), 7.72 (d, J = 7.5 Hz, 2H, ArH), 7.28-7.11 (m, 9H, ArH, NH 2 ), 3.58 ( t, J = 7.0 Hz, 1H, CH), 3.10-2.97 (m, 2H, CH2 ), 2.94 (dd, J = 7.0, 13.5 Hz, 1H, CH2 ), 2.76 (dd, J = 7.0, 13.5 Hz, 1H, CH2 ), 2.49-2.46 (m, 2H, CH2 ), 1.65-1.59 (m, 2H, CH2 ).
(実施例36)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.51 (d, J = 8.0 Hz, 2H, ArH), 7.35 (dd, J = 7.5, 9.0 Hz, 2H, ArH), 7.24 (d, J = 7.5 Hz, 2H, ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.81 (d, J = 8.0 Hz, 2H, ArH), 4.19 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.83 (m, 1H, CH2), 3.75 (m, 1H, CH2), 3.55 (m, 1H, CH2), 3.28 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.22 (m, 1H, CH2), 3.05 (dd, J = 10.0, 13.5 Hz, 1H, CH2).
(Example 36)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O): δ 7.51 (d, J = 8.0 Hz, 2H, ArH), 7.35 (dd, J = 7.5, 9.0 Hz, 2H, ArH), 7.24 (d, J = 7.5 Hz, 2H , ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.81 (d, J = 8.0 Hz, 2H, ArH), 4.19 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.83 ( m, 1H, CH 2 ), 3.75 (m, 1H, CH 2 ), 3.55 (m, 1H, CH 2 ), 3.28 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.22 (m, 1H , CH 2 ), 3.05 (dd, J = 10.0, 13.5 Hz, 1H, CH 2 ).
(実施例37)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 8.42 (brs, 2H), 8.21 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H, ArH), 7.27-7.24 (m, 2H, ArH), 7.16-7.13 (m, 5H, ArH), 3.71 (t, J = 7.0 Hz, 1H, CH), 3.09 (m, 1H, CH2), 3.00-2.92 (m, 2H, CH2), 2.84 (dd, J = 7.0, 13.5 Hz, 1H, CH2), 1.47-1.41 (m, 2H, CH2), 1.34-1.26 (m, 2H, CH2), 1.05 (t, J = 7.0 Hz, 2H, CH2).
(Example 37)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 8.42 (brs, 2H), 8.21 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H, ArH), 7.27-7.24 (m, 2H, ArH), 7.16-7.13 (m, 5H, ArH), 3.71 (t, J = 7.0 Hz, 1H, CH), 3.09 (m, 1H, CH2 ), 3.00-2.92 (m, 2H, CH2 ), 2.84 (dd, J = 7.0, 13.5 Hz, 1H, CH2 ), 1.47-1.41 (m, 2H, CH2 ), 1.34-1.26 (m, 2H, CH2 ), 1.05 (t, J = 7.0 Hz, 2H, CH2 ).
(実施例38)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 1.66-1.71 (m, 2H, CH2
CH
2 CH2), 3.04-3.11 (m, 2H, CH
2 CH2CH2), 3.31 (dd, J = 5.5, 13.0 Hz, 1H, β-H), 3.44-3.53 (m, 3H, β-H+CH2CH2
CH
2 ), 4.25 (dd, J = 6.0, 10.0 Hz, 1H, α-H), 6.85 (d, J = 8.0 Hz, 2H, ArH), 7.05 (t, J = 7.5 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.0 Hz, 2H, ArH), 7.66 (d, J = 7.5 Hz, 2H, ArH).
(Example 38)
The following compounds were prepared in the same manner as in Example 1.
1H NMR (3.5% DCl in D2O ); 1.66-1.71 (m, 2H , CH2CH2CH2 ) , 3.04-3.11 (m, 2H , CH2CH2CH2 ) , 3.31 ( dd, J = 5.5, 13.0 Hz, 1H, β-H), 3.44-3.53 (m, 3H, β-H+CH 2 CH 2 CH 2 ), 4.25 (dd, J = 6.0, 10.0 Hz, 1H, α-H) , 6.85 (d, J = 8.0 Hz, 2H, ArH), 7.05 (t, J = 7.5 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.0 Hz, 2H, ArH), 7.66 (d, J = 7.5 Hz, 2H, ArH).
(実施例39)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 1.66-1.72 (m, 2H, CH2
CH
2 CH2), 2.99-3.10 (m, 4H, CH
2 CH2
CH
2 ), 3.27 (dd, J = 6.5 Hz, 14.0, 1H, β-H), 3.35 (d, J = 10.5, 14.0 Hz, 1H, β-H), 4.17 (dd, J = 6.0, 10.5 Hz, 1H, α-H), 7.26 (d, J = 8.0 Hz, 2H, Ar), 7.38-7.40 (m, 2H, ArH), 7.58-7.62 (m, 5H, ArH).
(Example 39)
The following compounds were prepared in the same manner as in Example 1.
1H NMR (3.5% DCl in D2O ); 1.66-1.72 ( m , 2H , CH2CH2CH2 ) , 2.99-3.10 (m, 4H , CH2CH2CH2 ) , 3.27 (dd, J = 6.5 Hz, 14.0, 1H, β-H), 3.35 (d, J = 10.5, 14.0 Hz, 1H, β-H), 4.17 (dd, J = 6.0, 10.5 Hz, 1H, α-H), 7.26 (d, J = 8.0 Hz, 2H, ArH), 7.38-7.40 (m, 2H, ArH), 7.58-7.62 (m, 5H, ArH).
(実施例40)
実施例1と同様に下記化合物を調製した。
1H NMR (3.5% DCl in D2O); 1.42-1.50 (m, 2H, CH2
CH
2 CH2), 2.39-2.47 (m, 2H, CH2
CH
2 CH2), 2.96 (dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.06 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 3.31-3.39 (m, 2H, CH
2 CH2CH2), 4.24 (dd, J = 6.0, 10.0 Hz, 1H, α-H), 7.26-7.31 (m, 5H, ArH), 7.35-7.38 (m, 2H, ArH), 7.68 (d, J = 8.0 Hz, 2H, ArH).
(Example 40)
The following compounds were prepared in the same manner as in Example 1.
1H NMR (3.5% DCl in D2O ); 1.42-1.50 ( m , 2H , CH2CH2CH2 ) , 2.39-2.47 ( m, 2H , CH2CH2CH2 ) , 2.96 ( dd, J = 6.0, 13.5 Hz, 1H, β-H), 3.06 (dd, J = 10.0, 13.5 Hz, 1H, β-H), 3.31-3.39 (m, 2H, CH 2 CH 2 CH 2 ), 4.24 (dd , J = 6.0, 10.0 Hz, 1H, α-H), 7.26-7.31 (m, 5H, ArH), 7.35-7.38 (m, 2H, ArH), 7.68 (d, J = 8.0 Hz, 2H, ArH) .
(実施例41)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.42-4.37 (m, 2H, CH2), 4.11 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.31 (m, 1H, CH2), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.17 (m, 1H, CH2), 3.07-2.94 (m, 3H, CH2), 1.58-1.46 (m, 2H, CH2).
(Example 41)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.45-7.34 (m, 5H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 4.42. -4.37 (m, 2H, CH2 ), 4.11 (dd, J = 6.0, 10.0 Hz, 1H, CH), 3.31 (m, 1H, CH2 ), 3.25 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.17 (m, 1H, CH 2 ), 3.07-2.94 (m, 3H, CH 2 ), 1.58-1.46 (m, 2H, CH 2 ).
(実施例42)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 8.47-8.43 (m, 2H, ArH), 7.75 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.70 (dt, J = 2.5, 8.0 Hz, 1H, ArH), 7.50 (d, J = 9.0 Hz, 1H, ArH), 7.38 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.60 (dd, J = 7.0, 8.0 Hz, 1H, CH), 3.45 (dd, J = 7.0, 14.0 Hz, 1H, CH2), 3.36 (dd, J = 8.0, 14.0 Hz, 1H, CH2).
(Example 42)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O): δ 8.47-8.43 (m, 2H, ArH), 7.75 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.70 (dt, J = 2.5, 8.0 Hz, 1H, ArH), 7.50 (d, J = 9.0 Hz, 1H, ArH), 7.38 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.60 (dd, J = 7.0, 8.0 Hz, 1H, CH), 3.45 (dd, J = 7.0, 14.0 Hz, 1H, CH2 ), 3.36 (dd, J = 8.0, 14.0 Hz, 1H, CH2 ).
(実施例43)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 8.65 (dd, J = 2.0, 5.5 Hz, 1H, ArH), 8.45 (dt, J = 2.0, 8.5 Hz, 1H, ArH), 7.97 (dt, J = 2.0, 7.5 Hz, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.5 Hz, 1H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 4.80 (d, J = 16.5 Hz, 1H, CH2), 4.49 (d, J = 16.5 Hz, 1H, CH2), 4.34 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.33 (dd, J = 6.5, 13.5 Hz, 1H, CH2), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, CH2).
(Example 43)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O): δ 8.65 (dd, J = 2.0, 5.5 Hz, 1H, ArH), 8.45 (dt, J = 2.0, 8.5 Hz, 1H, ArH), 7.97 (dt, J = 2.0, 7.5 Hz, 1H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.5 Hz, 1H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 4.80 (d, J = 16.5 Hz, 1H, CH2 ), 4.49 (d, J = 16.5 Hz, 1H, CH2 ), 4.34 (dd, J = 6.5, 9.5 Hz, 1H, CH), 3.33 (dd, J = 6.5, 13.5 Hz, 1H, CH2 ), 3.12 (dd, J = 9.5, 13.5 Hz, 1H, CH2 ).
(実施例44)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 9.19 (s, 1H, ArH), 8.59 (d, J = 3.0 Hz, 1H, ArH), 8.36 (d, J = 9.0 Hz, 1H, ArH), 8.04 (dd, J = 3.0, 9.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 4.50 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH2).
(Example 44)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 9.19 (s, 1H, ArH), 8.59 (d, J = 3.0 Hz, 1H, ArH), 8.36 (d, J = 9.0 Hz, 1H, ArH), 8.04 (dd , J = 3.0, 9.0 Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH), 4.50 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH 2 ).
(実施例45)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 8.71 (d, J = 8.0 Hz, 1H, ArH), 8.52 (s, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 7.95 (t, J = 8.0 Hz, 1H, ArH), 7.58 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.20 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.67 (m, 1H, CH), 4.28-4.23 (m, 2H, CH2), 3.33 (dd, J = 6.0, 13.5 Hz, 1H, CH2), 3.06 (t, J = 10.0 Hz, 1H, CH2).
(Example 45)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (D 2 O): δ 8.71 (d, J = 8.0 Hz, 1H, ArH), 8.52 (s, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 7.95 (t , J = 8.0 Hz, 1H, ArH), 7.58 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 7.20 (dd, J = 3.0, 8.5 Hz, 2H, ArH), 4.67 (m, 1H, CH ), 4.28-4.23 (m, 2H, CH 2 ), 3.33 (dd, J = 6.0, 13.5 Hz, 1H, CH 2 ), 3.06 (t, J = 10.0 Hz, 1H, CH 2 ).
(実施例46)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 8.59 (m, 2H, ArH), 8.01 (m, 2H, ArH), 7.71 (m, 2H, ArH), 7.34 (m, 2H, ArH), 4.51 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH2).
(Example 46)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 8.59 (m, 2H, ArH), 8.01 (m, 2H, ArH), 7.71 (m, 2H, ArH), 7.34 (m, 2H, ArH), 4.51 (t, J = 7.5 Hz, 1H, CH), 3.37 (d, J = 7.5 Hz, 2H, CH 2 ).
(実施例47)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 8.43 (d, J = 5.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 2H, ArH), 7.19-7.16 (m, 4H, ArH), 4.43-4.33 (m, 3H, CH2, CH), 3.04-2.95 (m, 2H, CH2).
(Example 47)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 8.43 (d, J = 5.5 Hz, 2H, ArH), 7.56 (d, J = 7.5 Hz, 2H, ArH), 7.19-7.16 (m, 4H, ArH), 4.43. -4.33 (m, 3H, CH2 , CH), 3.04-2.95 (m, 2H, CH2 ).
(実施例48)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 8.96 (t, J = 6.0 Hz, 1H), 8.41 (brs, 2H), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.38 (dd, J = 1.0, 5.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.92 (dd, J = 3.5, 5.0 Hz, 1H, ArH), 6.83 (d, J = 1.5 Hz, 1H, ArH), 4.47 (dd, J = 6.0, 15.0 Hz, 1H, CH2), 4.39 (dd, J = 6.0, 15.0 Hz, 1H, CH2), 3.86 (t, J = 6.5 Hz, 1H, CH), 3.02 (dd, J = 6.5, 14.0 Hz, 1H, CH2), 2.90 (dd, J = 6.5, 14.0 Hz, 1H, CH2).
(Example 48)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 8.96 (t, J = 6.0 Hz, 1H), 8.41 (brs, 2H), 7.69 (d, J = 8.0 Hz, 2H, ArH), 7.38 (dd, J = 1.0, 5.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 6.92 (dd, J = 3.5, 5.0 Hz, 1H, ArH), 6.83 (d, J = 1.5 Hz, 1H , ArH), 4.47 (dd, J = 6.0, 15.0 Hz, 1H, CH2 ), 4.39 (dd, J = 6.0, 15.0 Hz, 1H, CH2 ), 3.86 (t, J = 6.5 Hz, 1H, CH2) ), 3.02 (dd, J = 6.5, 14.0 Hz, 1H, CH 2 ), 2.90 (dd, J = 6.5, 14.0 Hz, 1H, CH 2 ).
(実施例49)
実施例1と同様に下記化合物を調製した。
1H NMR (D2O): δ 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.33 (t, J = 8.5 Hz, 1H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH), 6.92-6.84 (m, 3H, ArH), 3.78 (s, 3H, CH3), 3.39 (d, J = 14.0 Hz, 1H, CH2), 3.25 (d, J = 14.0 Hz, 1H, CH2), 1.79 (s, 3H, CH3).
(Example 49)
The following compounds were prepared in the same manner as in Example 1.
1H NMR ( D2O ): δ 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.33 (t, J = 8.5 Hz, 1H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH ), 6.92-6.84 (m, 3H, ArH), 3.78 (s, 3H, CH3 ), 3.39 (d, J = 14.0 Hz, 1H, CH2 ), 3.25 (d, J = 14.0 Hz, 1H, CH 2 ), 1.79 (s, 3H, CH3 ).
(実施例50)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 10.29 (s, 1H), 8.67 (brs, 4H), 7.79 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.30 (d, J = 7.5 Hz, 1H, ArH), 7.22 (t, J = 8.0 Hz, 1H, ArH), 7.10 (t, J = 4.5 Hz, 1H, ArH), 7.00 (dd, J = 2.0, 8.0 Hz, 1H, ArH), 6.69 (dd, J = 3.0, 8.5 Hz, 1H, ArH), 4.14 (brs, 1H, CH), 3.71 (s, 3H, CH3), 3.29 (dd, J = 5.5, 14.0 Hz, 1H, CH2), 3.22 (d, J = 9.0, 14.0 Hz, 1H, CH2).
(Example 50)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 10.29 (s, 1H), 8.67 (brs, 4H), 7.79 (s, 1H, ArH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.30 ( d, J = 7.5 Hz, 1H, ArH), 7.22 (t, J = 8.0 Hz, 1H, ArH), 7.10 (t, J = 4.5 Hz, 1H, ArH), 7.00 (dd, J = 2.0, 8.0 Hz , 1H, ArH), 6.69 (dd, J = 3.0, 8.5 Hz, 1H, ArH), 4.14 (brs, 1H, CH), 3.71 (s, 3H, CH3 ), 3.29 (dd, J = 5.5, 14.0 Hz, 1H, CH2 ), 3.22 (d, J = 9.0, 14.0 Hz, 1H, CH2 ).
(実施例51)
実施例1と同様に下記化合物を調製した。
1H NMR (DMSO-d6): δ 10.18 (s, 1H), 8.52 (brs, 4H), 7.80 (d, J = 1.0 Hz, 1H, ArH), 7.64 (dd, J = 0.5, 7.5 Hz, 1H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.12 (d, J = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 6.78 (dd, J = 2.0, 8.0 Hz, 1H, ArH), 6.00 (s, 2H, CH2), 4.07 (brs, 1H, CH), 3.27 (dd, J = 8.0, 13.5 Hz, 1H, CH2), 3.20 (dd, J = 7.5, 13.5 Hz, 1H, CH2).
(Example 51)
The following compounds were prepared in the same manner as in Example 1.
1 H NMR (DMSO-d 6 ): δ 10.18 (s, 1H), 8.52 (brs, 4H), 7.80 (d, J = 1.0 Hz, 1H, ArH), 7.64 (dd, J = 0.5, 7.5 Hz, 1H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.12 (d, J = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 6.78 (dd , J = 2.0, 8.0 Hz, 1H, ArH), 6.00 (s, 2H, CH 2 ), 4.07 (brs, 1H, CH), 3.27 (dd, J = 8.0, 13.5 Hz, 1H, CH 2 ), 3.20 (dd, J = 7.5, 13.5Hz, 1H, CH2 ).
(実施例52)
(S)-3-(4-ボロノ-2-フルオロフェニル)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(1.00g,3.06mmol)にN,N-ジメチルホルムアミド(3.1mL)を加えた。この溶液にトリエチルアミン(341mg,3.37mmol)、m-アニシジン(415mg,3.37mmol)、1-ヒドロキシベンゾトリアゾール(454mg,3.37mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(646mg,3.37mmol)を氷浴下で加え、室温に昇温した。20時間攪拌後、水(10mL)を加え反応を停止し、酢酸エチル(50mL)で抽出した。有機相を飽和重曹水(10mL)、1%塩酸(10mL)、飽和食塩水(10mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後濾過し、濾液を減圧濃縮した。得られた粗生成物にジイソプロピルエーテル(30mL)を加え結晶化させ吸引濾過後、ジイソプロピルエーテル(30mL)で洗浄することで(S)-(4-(2-((tert-ブトキシカルボニル)アミノ)-3-((3-メトキシフェニル)アミノ)-3-オキソプロピル)-3-フルオロフェニル)ボロン酸(700 mg)を白色固体として得た。
得られた縮合体(700mg)にトリフルオロ酢酸(3.69g,32.4mmol)を加えた。16時間後、減圧濃縮し、さらにトルエン(20mLx3)を加えて減圧共沸させることでトリフルオロ酢酸を留去した。得られた固体をクロロホルム(50mL)を洗浄溶媒に用いて濾過し、洗浄することで(S)-(4-(2-アミノ-3-((3-メトキシフェニル)アミノ)-3-オキソプロピル)-3-フルオロフェニル)ボロン酸(754mg,1.68mmol,55%for 2 steps)を淡黄色固体として得た。
1H NMR (D2O): δ 7.43-7.37 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 6.77-6.75 (m, 2H, ArH), 6.69 (m, 1H, ArH), 4.26 (m, 1H, CH), 3.71 (s, 3H, CH3), 3.36 (m, 1H, CH2), 3.20 (m, 1H, CH2).
(Example 52)
Trifluoroacetic acid (3.69 g, 32.4 mmol) was added to the resulting condensate (700 mg). After 16 hours, the mixture was concentrated under reduced pressure, and toluene (20 mL×3) was further added and azeotroped under reduced pressure to distill off trifluoroacetic acid. The resulting solid was filtered using chloroform (50 mL) as a washing solvent and washed to give (S)-(4-(2-amino-3-((3-methoxyphenyl)amino)-3-oxopropyl )-3-Fluorophenyl)boronic acid (754 mg, 1.68 mmol, 55% for 2 steps) was obtained as a pale yellow solid.
1H NMR ( D2O ): δ 7.43-7.37 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 6.77-6.75 (m, 2H, ArH), 6.69 (m, 1H, ArH ), 4.26 (m, 1H, CH), 3.71 (s, 3H, CH3 ), 3.36 (m, 1H, CH2 ), 3.20 (m, 1H, CH2 ).
[取込み試験1]
(1)ヒトLAT1及びLAT2高発現HEK293細胞株の作製
Khunweeraphong,Nらの論文(Journal of Pharmacology Science, 2012, vol. 119, pp 368-380)に記載の方法に従って、ヒトLAT1及びLAT2を安定的に高発現するHEK293細胞をそれぞれ作製する。
アンピシリン及びネオマイシン耐性マーカーを有し、ヒトLAT1もしくはLAT2の全長cDNAをCMV(サイトメガロウィルス)のプロモーター下に挿入した、シャトルベクターDNA(LAT1:EX-H4509-M02、LAT2:EX-U0514-M02、GeneCopoeia社製)を構築する。このベクターを、HEK293細胞にリポフェクタミン(登録商標)2000(インビトロジェン)を用いた方法により、製造者の指示に従って遺伝子導入する。その後0.9mg/mL Geneticin(登録商標)存在下限界希釈法にて導入遺伝子の安定発現細胞クローンを選択し、L-ボロノフェニルアラニン(L-BPA)の取り込みが遺伝子導入前のHEK293細胞に比べて2~5倍程度亢進した細胞クローンを取得する。この細胞を継代してLAT1及びLAT2選択的取り込みの評価に用いる。
[Uptake test 1]
(1) Preparation of human LAT1 and LAT2 high expression HEK293 cell lines Khunweeraphong, N et al.'s paper (Journal of Pharmacology Science, 2012, vol. 119, pp 368-380) according to the method described in, human LAT1 and LAT2 stably Each HEK293 cell that highly expresses is generated.
Shuttle vector DNA (LAT1: EX-H4509-M02, LAT2: EX-U0514-M02, GeneCopoeia). This vector is transfected into HEK293 cells by a method using Lipofectamine (registered trademark) 2000 (Invitrogen) according to the manufacturer's instructions. After that, cell clones stably expressing the transgene were selected by limiting dilution in the presence of 0.9 mg/mL Geneticin (registered trademark), and L-boronophenylalanine (L-BPA) uptake was compared to HEK293 cells before gene transfer. Cell clones with 2- to 5-fold enhancement are obtained. The cells are passaged and used to assess LAT1 and LAT2 selective uptake.
(2)LAT1及びLAT2選択的取り込みの評価
細胞の取り込みの評価方法はKhunweeraphong,Nらの論文(Journal of Pharmacology Science,2012, vol.119,pp 368-380)と同様の手法を用いる。(1)で取得したそれぞれの細胞を用いて、評価する。ただし、放射性同位元素は使用せず、基質濃度0.1mM、LAT1及びLAT2阻害剤として2mM BCH(2-アミノ-2-ノルボンナンカルボン酸)を使用し、反応後の細胞を0.05% Tween20で回収して得られた細胞液のボロノフェニルアラニンアミド誘導体の濃度を求める。
細胞内のボロノフェニルアラニンアミド誘導体の定量はHattori,Yらの論文(Sensors 2017,17,2436)に記載の方法に従い、ホウ素センサーとして2-(2-ヒドロキシフェニル)ピリジン(ホウ素センサー5)を用いて実施する。
細胞取り込みの評価に際しては、実験間の変動を考慮し、同日に実施する比較対象であるL-BPAの取り込みに対する相対値(LAT1選択性)として評価する。
LAT1選択性=(LAT1細胞における化合物の取り込み定量値/LAT1細胞におけるコントロールLBPAの取り込み定量値)/(LAT2細胞における化合物の取り込み定量値/LAT2細胞におけるコントロールLBPAの取り込み定量値)
(2) Evaluation of LAT1 and LAT2 Selective Uptake As a method for evaluating cellular uptake, the same method as described in Khunweeraphong, N et al. (Journal of Pharmacology Science, 2012, vol.119, pp 368-380) is used. Each cell obtained in (1) is used for evaluation. However, no radioisotope was used, the substrate concentration was 0.1 mM, 2 mM BCH (2-amino-2-norbonnanecarboxylic acid) was used as LAT1 and LAT2 inhibitors, and the cells after the reaction were added to 0.05%. The concentration of the boronophenylalanine amide derivative in the cell fluid obtained by collecting with Tween 20 is determined.
Boronophenylalanine amide derivatives in cells are quantified according to the method described in Hattori, Y et al. (Sensors 2017, 17, 2436), using 2-(2-hydroxyphenyl)pyridine (boron sensor 5) as a boron sensor. to implement.
Cellular uptake is evaluated as a relative value (LAT1 selectivity) with respect to the uptake of L-BPA, which is a comparative control, performed on the same day, taking into consideration inter-experimental variability.
LAT1 selectivity = (quantitative compound uptake in LAT1 cells/quantitative control LBPA uptake in LAT1 cells)/(quantitative compound uptake in LAT2 cells/quantitative control LBPA uptake in LAT2 cells)
[取込み試験2]
(1)腫瘍細胞への取込み評価試験
(生物学的評価2)
1.5x106個のヒト舌ガン細胞(SAS細胞)、ヒトグリオーマ細胞(A172細胞)またはヒト乳がん細胞(MCF-7)を100mmディッシュに播種し、37℃、5%CO2雰囲気下で24時間、前培養を行なった。培養液を吸引除去し、各実施例又は参考例の薬剤を1mM含む培養液を加え、37℃、5%CO2雰囲気下で3時間暴露培養を行なった。培養液を吸引除去後、PBSを用いて細胞を1回洗浄した後に、トリプシン処理を行い、細胞を回収した。回収した細胞数をカウントし、遠心分離によりパックした後、HClO4(60%、0.3mL)とH2O2(31%、0.6mL)を加えて、一晩、75℃に加熱して灰化溶液を作成した。灰化溶液を純水で5mLにフィルアップした後5Cのろ紙を用いてろ過し、Agilent社710 ICP-ОESを用いて溶液中のホウ素濃度を測定することによって、細胞107個当たりのホウ素量(μg)を求めた。細胞取り込みの評価に際しては、実験間の変動を考慮し、同日に実施する比較対象である参考例のL-BPAの取り込みに対する相対値として評価する。
[Uptake test 2]
(1) Evaluation test for uptake into tumor cells (biological evaluation 2)
1.5×10 6 human tongue cancer cells (SAS cells), human glioma cells (A172 cells) or human breast cancer cells (MCF-7) were seeded in a 100 mm dish and incubated at 37° C. in a 5% CO 2 atmosphere for 24 hours. , was pre-cultured. The culture solution was removed by aspiration, a culture solution containing 1 mM of the drug of each example or reference example was added, and exposure culture was carried out at 37° C. in a 5% CO 2 atmosphere for 3 hours. After removing the culture medium by aspiration, the cells were washed once with PBS and then trypsinized to collect the cells. After counting the number of harvested cells and packing by centrifugation, HClO 4 (60%, 0.3 mL) and H 2 O 2 (31%, 0.6 mL) were added and heated to 75° C. overnight. to prepare an ashing solution. After filling up the ashing solution with pure water to 5 mL, it was filtered using 5C filter paper, and the boron concentration in the solution was measured using Agilent 710 ICP-OES to determine the amount of boron per 10 7 cells. (μg) was obtained. In the evaluation of cell uptake, taking account of inter-experimental variation, the value is evaluated relative to the uptake of L-BPA of Reference Example, which is a comparative example performed on the same day.
取り込み試験の結果を表に示す。ここで、比較対照にはBNCTの臨床研究に使用されている4-ボロノ-L-フェニルアラニン(L-BPA)を設定した。 The results of the uptake test are shown in the table. Here, 4-borono-L-phenylalanine (L-BPA), which is used in clinical studies of BNCT, was set as a control for comparison.
その結果、本発明の化合物の多くは、BPAと比較して、同濃度の処理で同等以上に細胞に取り込まれることがわかった。 As a result, it was found that many of the compounds of the present invention were taken up into cells at the same concentration or higher than BPA when treated at the same concentration.
主な化合物のその他の取りこみについての結果を以下の表に示す。表中、取込みA:BPAより3倍以上高い、B:BPAと同等~3倍未満、C:取り込まれるが、BPAより低い意味を表わす。
(以下の表において、特に記載がない限り、L体を表すものとする)
Results for other uptakes of the main compounds are shown in the table below. In the table, uptake A: 3-fold higher than BPA, B: equal to less than 3-fold higher than BPA, C: uptake but lower than BPA.
(In the following tables, unless otherwise specified, the L form is represented)
なお、表1~8については、下記で示される化合物の各置換基を置換基別に示している。
表から明らかな通り、実施例の化合物は、腫瘍細胞に対して、取り込み能が優れていることが示された。表9に示す化合物は、とりわけ、PC3細胞及びLNCap細胞に取り込まれる能力が高い。PC3細胞はLAT1が高発現し、LNCap細胞はLAT1が発現していないことが知られており(参考文献:The Prostate 77:222-233(2017))、この結果から、これらの化合物は、LAT1を経由せず、その他の機構で取り込まれる可能性が示唆された。
As is clear from the table, the compounds of Examples were shown to have excellent uptake ability into tumor cells. The compounds shown in Table 9 are particularly capable of being taken up by PC3 and LNCap cells. LAT1 is highly expressed in PC3 cells, LNCap cells are known to not express LAT1 (reference: The Prostate 77: 222-233 (2017)), from this result, these compounds, LAT1 It was suggested that it may be taken up by other mechanisms without going through
Claims (7)
R1、R2は、B原子と共に、ボロン酸(‐B(OH)2)、ボロン酸エステル、又はボロン酸アミドの置換基を表し;
R3は、H、ハロゲン、ヒドロキシ、シアノ、アミノ、C1-C6アルキルアミノ、C1-C6アルキル、C1-C6アルコキシ、ベンジルオキシ、C1-C6アルコキシC1-C6アルキル、ニトロ、C1-C6ハロアルキル、カルバモイル、C1-C6アルキルアミノカルボニル、C1-C6アルコキシカルボニル、C1-C6アルキルカルボニル、COOR10(R10は、H又はC1-C6アルキル、アミノ、C1-C6アルキルアミノ)、C1-C6ハロアルキルスルファニル、C1-C6ハロアルキルスルフィニル、C1-C6ハロアルキルスルホニル、C1-C6アルキルチオ、C1-C6アルキルスルフィニル、C1-C6アルキルスルホニル、アミノスルホニル、スルホ、及びスルファモイルからなる群から、独立して選択される基を表し;
sは、1~4のいずれかの整数を表し;
R4は、H、C1-C6アルキル、ベンジル、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表し;
R5は、H、置換もしくは非置換のC1-C6アルキル、置換もしくは非置換のC2-6アルケニル、置換もしくは非置換のC2-6アルキニル、ヒドロキシ、シアノ、置換もしくは非置換のアミノ、置換もしくは非置換のC1-C6アルコキシ、置換もしくは非置換のC1-C6アルコキシC1-C6アルキル、置換もしくは非置換のアシル、置換もしくは非置換のスルホニル、置換もしくは非置換のカルバモイル、C1-C6アルコキシカルボニル、置換もしくは非置換のC3-C7シクロアルキル、置換もしくは非置換のC3-C7シクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表すか、又は、R4R5がNと共に、置換もしくは非置換のC3-C7ヘテロシクロアルキルを形成し;
R6はH又は置換されていてもよいC1-C6アルキル、又は隣接するメチレン部とベンゼン環に縮合する形の環構造を形成してもよいことを表し、ここで、環構造は、非置換のC5-7シクロアルキル又は非置換のC5-7シクロアルケニルを表す。 A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
R 1 , R 2 together with the B atom represent substituents of boronic acid (-B(OH) 2 ), boronic ester, or boronic acid amide;
R 3 is H, halogen, hydroxy, cyano, amino, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, C1-C6 alkoxyC1-C6 alkyl, nitro, C1-C6 haloalkyl, carbamoyl , C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, COOR 10 (R 10 is H or C1-C6 alkyl, amino, C1-C6 alkylamino), C1-C6 haloalkylsulfanyl, C1 - represents a group independently selected from the group consisting of C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, aminosulfonyl, sulfo, and sulfamoyl;
s represents any integer from 1 to 4;
R 4 represents H, C1-C6 alkyl, benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, cyano, substituted or unsubstituted amino, substituted or unsubstituted substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy C1-C6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted carbamoyl, C1-C6 alkoxycarbonyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted unaromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or R 4 R 5 together with N form a substituted or unsubstituted C3-C7 heterocycloalkyl;
R 6 represents H or optionally substituted C1-C6 alkyl, or may form a fused ring structure with the adjacent methylene moiety and a benzene ring, wherein the ring structure is unsubstituted represents C5-7 cycloalkyl or unsubstituted C5-7 cycloalkenyl.
前記R5は、置換もしくは非置換のアリ一ル、又は置換もしくは非置換のへテロアリ一ルを表す、請求項1又は2に記載の化合物又はその薬学的に許容される塩。 said R 4 represents H or C1-C6 alkyl;
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein said R5 represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
前記R5は、アリール置換C1-C6アルキルを表す、請求項1又は2に記載の化合物又はその薬学的に許容される塩。 said R 4 represents H or C1-C6 alkyl;
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said R 5 represents aryl-substituted C1-C6 alkyl.
A radioactive isotope as a substituent at any one site of R 3 , R 4 or R 5 of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof Containing diagnostic agents.
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