JP2009533323A - Ｈｓｐ９０阻害剤として用いられるピロロピリミジン誘導体 - Google Patents

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Publication number

JP2009533323A

JP2009533323A JP2008558881A JP2008558881A JP2009533323A JP 2009533323 A JP2009533323 A JP 2009533323A JP 2008558881 A JP2008558881 A JP 2008558881A JP 2008558881 A JP2008558881 A JP 2008558881A JP 2009533323 A JP2009533323 A JP 2009533323A

Authority

JP

Japan

Prior art keywords

pyrrolo

pyrimidine

phenyl

alk

mmol

Prior art date

2006-03-11

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.)

Withdrawn

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• 239000003481 heat shock protein 90 inhibitor Substances 0.000 title description 14
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 248
• 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims abstract description 56
• 101710113864 Heat shock protein 90 Proteins 0.000 claims abstract description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
• 239000001257 hydrogen Substances 0.000 claims abstract description 19
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 19
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 17
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
• 201000011510 cancer Diseases 0.000 claims abstract description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
• 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 11
• 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 10
• 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract 3
• 238000000034 method Methods 0.000 claims description 139
• 201000006417 multiple sclerosis Diseases 0.000 claims description 114
• -1 methoxy, ethoxy, methylthio, ethylthio, hydroxyethylthio, methylamino, diethylaminomethylthio, methylaminocarbonylmethylthio Chemical group 0.000 claims description 90
• 230000000694 effects Effects 0.000 claims description 78
• 239000000203 mixture Substances 0.000 claims description 59
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 20
• 239000003814 drug Substances 0.000 claims description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
• 125000004122 cyclic group Chemical group 0.000 claims description 15
• 125000003277 amino group Chemical group 0.000 claims description 13
• 229940079593 drug Drugs 0.000 claims description 13
• 230000005764 inhibitory process Effects 0.000 claims description 13
• 150000003839 salts Chemical class 0.000 claims description 13
• 125000001424 substituent group Chemical group 0.000 claims description 13
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 238000001727 in vivo Methods 0.000 claims description 7
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• GPTFURBXHJWNHR-UHFFFAOYSA-N protopine Chemical compound C1=C2C(=O)CC3=CC=C4OCOC4=C3CN(C)CCC2=CC2=C1OCO2 GPTFURBXHJWNHR-UHFFFAOYSA-N 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 208000023105 Huntington disease Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 229910052801 chlorine Inorganic materials 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
• 208000024827 Alzheimer disease Diseases 0.000 claims description 3
• 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 3
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
• 201000009273 Endometriosis Diseases 0.000 claims description 3
• 206010021143 Hypoxia Diseases 0.000 claims description 3
• 206010062016 Immunosuppression Diseases 0.000 claims description 3
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
• 125000005336 allyloxy group Chemical group 0.000 claims description 3
• 230000033115 angiogenesis Effects 0.000 claims description 3
• 208000006673 asthma Diseases 0.000 claims description 3
• 210000004556 brain Anatomy 0.000 claims description 3
• 238000002512 chemotherapy Methods 0.000 claims description 3
• 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 201000011066 hemangioma Diseases 0.000 claims description 3
• 230000001506 immunosuppresive effect Effects 0.000 claims description 3
• 208000027866 inflammatory disease Diseases 0.000 claims description 3
• 208000037906 ischaemic injury Diseases 0.000 claims description 3
• 206010025135 lupus erythematosus Diseases 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 208000008864 scrapie Diseases 0.000 claims description 3
• 231100000419 toxicity Toxicity 0.000 claims description 3
• 230000001988 toxicity Effects 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• 230000003612 virological effect Effects 0.000 claims description 3
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 206010017533 Fungal infection Diseases 0.000 claims description 2
• 208000031888 Mycoses Diseases 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
• 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims 1
• 206010012601 diabetes mellitus Diseases 0.000 claims 1
• 239000000835 fiber Substances 0.000 claims 1
• 229910052731 fluorine Inorganic materials 0.000 abstract 1
• 150000002431 hydrogen Chemical class 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 186
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 168
• 239000000243 solution Substances 0.000 description 106
• 235000019439 ethyl acetate Nutrition 0.000 description 96
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• 239000007787 solid Substances 0.000 description 74
• 230000008569 process Effects 0.000 description 66
• 238000003818 flash chromatography Methods 0.000 description 62
• 238000004458 analytical method Methods 0.000 description 61
• 238000005481 NMR spectroscopy Methods 0.000 description 60
• 238000002875 fluorescence polarization Methods 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
• 239000012043 crude product Substances 0.000 description 47
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 43
• 239000000741 silica gel Substances 0.000 description 42
• 229910002027 silica gel Inorganic materials 0.000 description 42
• 239000000047 product Substances 0.000 description 41
• 239000011541 reaction mixture Substances 0.000 description 41
• 238000006243 chemical reaction Methods 0.000 description 39
• 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 37
• 239000011734 sodium Substances 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• 108090000623 proteins and genes Proteins 0.000 description 28
• 229910004298 SiO 2 Inorganic materials 0.000 description 27
• 102000004169 proteins and genes Human genes 0.000 description 25
• 239000002904 solvent Substances 0.000 description 24
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 23
• 210000004027 cell Anatomy 0.000 description 21
• 229920006395 saturated elastomer Polymers 0.000 description 21
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
• 239000000706 filtrate Substances 0.000 description 20
• 230000002209 hydrophobic effect Effects 0.000 description 19
• 239000003921 oil Substances 0.000 description 19
• 235000019198 oils Nutrition 0.000 description 19
• 239000012074 organic phase Substances 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 238000000746 purification Methods 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• 108010006519 Molecular Chaperones Proteins 0.000 description 15
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 13
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 235000019441 ethanol Nutrition 0.000 description 11
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• 150000003457 sulfones Chemical group 0.000 description 10
• AVIJWXRQYVQJOA-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound CSC1=NC(Cl)=C2C(C#N)=CN(COCC[Si](C)(C)C)C2=N1 AVIJWXRQYVQJOA-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000012467 final product Substances 0.000 description 9
• 238000004128 high performance liquid chromatography Methods 0.000 description 9
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 8
• 239000000284 extract Substances 0.000 description 8
• 230000006870 function Effects 0.000 description 8
• 125000006239 protecting group Chemical group 0.000 description 8
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
• 238000006467 substitution reaction Methods 0.000 description 8
• 102000005431 Molecular Chaperones Human genes 0.000 description 7
• 239000012267 brine Substances 0.000 description 7
• 230000008878 coupling Effects 0.000 description 7
• 238000010168 coupling process Methods 0.000 description 7
• 238000005859 coupling reaction Methods 0.000 description 7
• 238000006731 degradation reaction Methods 0.000 description 7
• 238000002953 preparative HPLC Methods 0.000 description 7
• ZURADLKPXCNTOX-UHFFFAOYSA-N 4-(4-fluoro-2-methylphenyl)-2-methylsulfonyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound CC1=CC(F)=CC=C1C1=NC(S(C)(=O)=O)=NC2=C1C(C#N)=CN2COCC[Si](C)(C)C ZURADLKPXCNTOX-UHFFFAOYSA-N 0.000 description 6
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
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• QTQAWLPCGQOSGP-KSRBKZBZSA-N geldanamycin Chemical class N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-KSRBKZBZSA-N 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• 239000012299 nitrogen atmosphere Substances 0.000 description 6
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
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• XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 description 6
• 230000001105 regulatory effect Effects 0.000 description 6
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
• IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 5
• ZZRABHYJVNMUBQ-UHFFFAOYSA-N 2-[[5-bromo-4-(2,4-dimethylphenyl)-2-methylsulfanylpyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl-trimethylsilane Chemical compound C=12C(Br)=CN(COCC[Si](C)(C)C)C2=NC(SC)=NC=1C1=CC=C(C)C=C1C ZZRABHYJVNMUBQ-UHFFFAOYSA-N 0.000 description 5
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• IWYINUMXTWMCHT-UHFFFAOYSA-N 4-(2,4-dichloro-5-methoxyphenyl)-2-methylsulfanyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound C1=C(Cl)C(OC)=CC(C=2C=3C(C#N)=CN(COCC[Si](C)(C)C)C=3N=C(SC)N=2)=C1Cl IWYINUMXTWMCHT-UHFFFAOYSA-N 0.000 description 4
• LXUVFEGNZXPXCA-UHFFFAOYSA-N 4-(2,4-dimethylphenyl)-2-methylsulfanyl-7h-pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound C=12C(C#N)=CNC2=NC(SC)=NC=1C1=CC=C(C)C=C1C LXUVFEGNZXPXCA-UHFFFAOYSA-N 0.000 description 4
• MQDAIEJXKVQTLR-UHFFFAOYSA-N 4-(2-chloro-4,5-dimethoxyphenyl)-2-methylsulfanyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile Chemical compound C1=C(OC)C(OC)=CC(Cl)=C1C1=NC(SC)=NC2=C1C(C#N)=CN2COCC[Si](C)(C)C MQDAIEJXKVQTLR-UHFFFAOYSA-N 0.000 description 4
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• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 4
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• 239000012044 organic layer Substances 0.000 description 4
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• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
• 125000000714 pyrimidinyl group Chemical group 0.000 description 4
• 125000006413 ring segment Chemical group 0.000 description 4
• 239000011780 sodium chloride Substances 0.000 description 4
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
• 235000019345 sodium thiosulphate Nutrition 0.000 description 4
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