JP2020019806A - インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス - Google Patents
インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス Download PDFInfo
- Publication number
- JP2020019806A JP2020019806A JP2019184589A JP2019184589A JP2020019806A JP 2020019806 A JP2020019806 A JP 2020019806A JP 2019184589 A JP2019184589 A JP 2019184589A JP 2019184589 A JP2019184589 A JP 2019184589A JP 2020019806 A JP2020019806 A JP 2020019806A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- amino
- tert
- reducing agent
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 177
- 230000008569 process Effects 0.000 title claims description 142
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 229940113303 Indoleamine 2,3-dioxygenase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 286
- -1 N-formylmethylaminosulfamoylcarbamate derivative Chemical class 0.000 claims abstract description 132
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 120
- 238000006243 chemical reaction Methods 0.000 claims description 97
- 239000000203 mixture Substances 0.000 claims description 92
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 79
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 77
- 239000002904 solvent Substances 0.000 claims description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 239000003638 chemical reducing agent Substances 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical group CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 30
- 125000006239 protecting group Chemical group 0.000 claims description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 26
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 150000007524 organic acids Chemical class 0.000 claims description 16
- 238000010511 deprotection reaction Methods 0.000 claims description 15
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- QFUUIYBSWTYLNT-UHFFFAOYSA-N tert-butyl N-[(4-methoxyphenyl)methyl]-N-[(4-methoxyphenyl)methyl-(2-oxoethyl)sulfamoyl]carbamate Chemical compound COc1ccc(CN(CC=O)S(=O)(=O)N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)cc1 QFUUIYBSWTYLNT-UHFFFAOYSA-N 0.000 claims description 8
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 7
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
- 239000003223 protective agent Substances 0.000 claims description 7
- VNDJTNFKQAFSLL-UHFFFAOYSA-N tert-butyl N-[2-oxoethyl(prop-2-enyl)sulfamoyl]-N-prop-2-enylcarbamate Chemical compound CC(C)(C)OC(=O)N(CC=C)S(=O)(=O)N(CC=C)CC=O VNDJTNFKQAFSLL-UHFFFAOYSA-N 0.000 claims description 7
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical group NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 claims description 7
- KGVDNTXHSSRDTB-UHFFFAOYSA-N ethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound CCOC(=O)NS(=O)(=O)NCC(OC)OC KGVDNTXHSSRDTB-UHFFFAOYSA-N 0.000 claims description 6
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims description 5
- IJIVZRMITPUVAC-UHFFFAOYSA-N 2,2,2-trichloroethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCC(Cl)(Cl)Cl)OC IJIVZRMITPUVAC-UHFFFAOYSA-N 0.000 claims description 5
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 abstract description 103
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 abstract description 103
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 42
- 206010028980 Neoplasm Diseases 0.000 abstract description 41
- 239000003112 inhibitor Substances 0.000 abstract description 29
- 238000011282 treatment Methods 0.000 abstract description 27
- 201000011510 cancer Diseases 0.000 abstract description 11
- GEHLUDKKFYJCCR-UHFFFAOYSA-N C1=CC(=C(C=C1N2C(=NOC2=O)C3=NON=C3NCCNNS(=O)(=O)NC(=O)O)Br)F Chemical class C1=CC(=C(C=C1N2C(=NOC2=O)C3=NON=C3NCCNNS(=O)(=O)NC(=O)O)Br)F GEHLUDKKFYJCCR-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 198
- 239000000243 solution Substances 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 44
- 239000007787 solid Substances 0.000 description 44
- 239000000047 product Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- 230000000694 effects Effects 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- 201000010099 disease Diseases 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- 241000699670 Mus sp. Species 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 150000008282 halocarbons Chemical class 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 150000003839 salts Chemical class 0.000 description 19
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000012267 brine Substances 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 229960004799 tryptophan Drugs 0.000 description 18
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 13
- 210000001744 T-lymphocyte Anatomy 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- ORHZJUSHZUCMKR-UHFFFAOYSA-N chembl565923 Chemical compound NC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 ORHZJUSHZUCMKR-UHFFFAOYSA-N 0.000 description 10
- 229940127089 cytotoxic agent Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 239000012351 deprotecting agent Substances 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 230000001506 immunosuppresive effect Effects 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 210000004980 monocyte derived macrophage Anatomy 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 108010002350 Interleukin-2 Proteins 0.000 description 8
- 102000000588 Interleukin-2 Human genes 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 102100037850 Interferon gamma Human genes 0.000 description 7
- 108010074328 Interferon-gamma Proteins 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 210000004443 dendritic cell Anatomy 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 229940127084 other anti-cancer agent Drugs 0.000 description 7
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- DNFUTAVRGAVUKE-UHFFFAOYSA-N 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide Chemical compound ON=C(N)C1=NON=C1N DNFUTAVRGAVUKE-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 230000001605 fetal effect Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 230000002163 immunogen Effects 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000035935 pregnancy Effects 0.000 description 6
- ZADWXFSZEAPBJS-UHFFFAOYSA-N racemic N-methyl tryptophan Natural products C1=CC=C2N(C)C=C(CC(N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 5
- 206010062016 Immunosuppression Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 239000003443 antiviral agent Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000000973 chemotherapeutic effect Effects 0.000 description 5
- 210000002865 immune cell Anatomy 0.000 description 5
- 210000000987 immune system Anatomy 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 210000001616 monocyte Anatomy 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- ACNRTYKOPZDRCO-UHFFFAOYSA-N tert-butyl n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC=O ACNRTYKOPZDRCO-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- ZADWXFSZEAPBJS-JTQLQIEISA-N 1-methyl-L-tryptophan Chemical compound C1=CC=C2N(C)C=C(C[C@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-JTQLQIEISA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 4
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000006052 T cell proliferation Effects 0.000 description 4
- 230000005867 T cell response Effects 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 210000000612 antigen-presenting cell Anatomy 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- BOWMUFROAFFZHM-UHFFFAOYSA-N ethyl 2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]acetate Chemical compound CCOC(=O)CNS(=O)(=O)NC(=O)OC(C)(C)C BOWMUFROAFFZHM-UHFFFAOYSA-N 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 238000002649 immunization Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 102000003390 tumor necrosis factor Human genes 0.000 description 4
- ZADWXFSZEAPBJS-SNVBAGLBSA-N (2r)-2-amino-3-(1-methylindol-3-yl)propanoic acid Chemical compound C1=CC=C2N(C)C=C(C[C@@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-SNVBAGLBSA-N 0.000 description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 3
- ZRHUHDUEXWHZMA-UHFFFAOYSA-N 1,4-dihydropyrazol-5-one Chemical compound O=C1CC=NN1 ZRHUHDUEXWHZMA-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 208000031886 HIV Infections Diseases 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 3
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000004946 alkenylalkyl group Chemical group 0.000 description 3
- 230000000735 allogeneic effect Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UXOLDCOJRAMLTQ-UTCJRWHESA-N ethyl (2z)-2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\Cl)=N\O UXOLDCOJRAMLTQ-UTCJRWHESA-N 0.000 description 3
- FZTJKCPVRKNACQ-UHFFFAOYSA-N ethyl 2-[(4-methoxyphenyl)methyl-[(4-methoxyphenyl)methyl-[(2-methylpropan-2-yl)oxycarbonyl]sulfamoyl]amino]acetate Chemical compound CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)N(Cc1ccc(OC)cc1)C(=O)OC(C)(C)C FZTJKCPVRKNACQ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 210000003754 fetus Anatomy 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000000971 hippocampal effect Effects 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003308 immunostimulating effect Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical group O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- NIDRYBLTWYFCFV-FMTVUPSXSA-N (+)-calanolide A Chemical compound C1=CC(C)(C)OC2=C1C(O[C@H](C)[C@@H](C)[C@@H]1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-FMTVUPSXSA-N 0.000 description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-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
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- KOWPUNQBGWIERF-UHFFFAOYSA-N 3-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Br)=C1 KOWPUNQBGWIERF-UHFFFAOYSA-N 0.000 description 2
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 description 2
- HUYOMBHZNMTQPT-UHFFFAOYSA-N 9H-fluoren-9-ylmethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCC1c2ccccc2-c2ccccc12)OC HUYOMBHZNMTQPT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102100036664 Adenosine deaminase Human genes 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
- 206010003694 Atrophy Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 102100025136 Macrosialin Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 230000006023 anti-tumor response Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 239000002027 dichloromethane extract Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- OMEINKSIRMRTJF-UHFFFAOYSA-N ethyl 2-[[(2-methylpropan-2-yl)oxycarbonyl-prop-2-enylsulfamoyl]-prop-2-enylamino]acetate Chemical compound CCOC(=O)CN(CC=C)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C OMEINKSIRMRTJF-UHFFFAOYSA-N 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 238000010191 image analysis Methods 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000008774 maternal effect Effects 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000002981 neuropathic effect Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000001282 organosilanes Chemical class 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 229940074439 potassium sodium tartrate Drugs 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229960000311 ritonavir Drugs 0.000 description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 230000000862 serotonergic effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 210000004988 splenocyte Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 2
- KAJZZLBZXOBEMD-UHFFFAOYSA-N tert-butyl n-chlorosulfonylcarbamate Chemical compound CC(C)(C)OC(=O)NS(Cl)(=O)=O KAJZZLBZXOBEMD-UHFFFAOYSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 230000003614 tolerogenic effect Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229960004854 viral vaccine Drugs 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- VIESAWGOYVNHLV-UHFFFAOYSA-N 1,3-dihydropyrrol-2-one Chemical compound O=C1CC=CN1 VIESAWGOYVNHLV-UHFFFAOYSA-N 0.000 description 1
- WBNTUGPRADFXAL-UHFFFAOYSA-N 1H-pyrazole-5-carboximidamide Chemical class NC(=N)C=1C=CNN=1 WBNTUGPRADFXAL-UHFFFAOYSA-N 0.000 description 1
- ASOMNDIOOKDVDC-UHFFFAOYSA-N 1h-indol-2-yl-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl]methanone Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=CC=C3C=2)CC1 ASOMNDIOOKDVDC-UHFFFAOYSA-N 0.000 description 1
- KPWDGTGXUYRARH-UHFFFAOYSA-N 2,2,2-trichloroethanol Chemical compound OCC(Cl)(Cl)Cl KPWDGTGXUYRARH-UHFFFAOYSA-N 0.000 description 1
- UZYQSNQJLWTICD-UHFFFAOYSA-N 2-(n-benzoylanilino)-2,2-dinitroacetic acid Chemical compound C=1C=CC=CC=1N(C(C(=O)O)([N+]([O-])=O)[N+]([O-])=O)C(=O)C1=CC=CC=C1 UZYQSNQJLWTICD-UHFFFAOYSA-N 0.000 description 1
- GWFOVSGRNGAGDL-FSDSQADBSA-N 2-amino-9-[(1r,2r,3s)-2,3-bis(hydroxymethyl)cyclobutyl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1C[C@H](CO)[C@H]1CO GWFOVSGRNGAGDL-FSDSQADBSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- ZSTVBWKWXBVZJB-UHFFFAOYSA-N 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-one Chemical compound NC1=NON=C1C1=NOC(=O)N1C1=CC=C(F)C(Br)=C1 ZSTVBWKWXBVZJB-UHFFFAOYSA-N 0.000 description 1
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 description 1
- HWYPORXMNMOVEE-UHFFFAOYSA-N 3-[4-(2-aminoethylamino)-1,2,5-oxadiazol-3-yl]-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-one;hydrochloride Chemical compound Cl.NCCNC1=NON=C1C1=NOC(=O)N1C1=CC=C(F)C(Br)=C1 HWYPORXMNMOVEE-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- ATCRIOJPQXDFNY-ZETCQYMHSA-N 6-chloro-2-(1-furo[2,3-c]pyridin-5-yl-ethylsulfanyl)-pyrimidin-4-ylamine Chemical compound S([C@@H](C)C=1N=CC=2OC=CC=2C=1)C1=NC(N)=CC(Cl)=N1 ATCRIOJPQXDFNY-ZETCQYMHSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WRGDDDWWOQOVKI-UHFFFAOYSA-N 9H-fluoren-9-ylmethyl N-[2-[[4-[4-(3-bromo-4-fluorophenyl)-5-oxo-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl]amino]ethylsulfamoyl]carbamate Chemical compound Fc1ccc(cc1Br)-n1c(noc1=O)-c1nonc1NCCNS(=O)(=O)NC(=O)OCC1c2ccccc2-c2ccccc12 WRGDDDWWOQOVKI-UHFFFAOYSA-N 0.000 description 1
- 101150053137 AIF1 gene Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 101100002068 Bacillus subtilis (strain 168) araR gene Proteins 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229910014265 BrCl Inorganic materials 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 238000010599 BrdU assay Methods 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 1
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 1
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 1
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 241000287497 Calypte Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 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 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 1
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- MEPWYMZXCZXDKA-UHFFFAOYSA-N NC=1C(=NON1)C(N(C1=CC(=C(C=C1)F)Br)CC)=NO Chemical compound NC=1C(=NON1)C(N(C1=CC(=C(C=C1)F)Br)CC)=NO MEPWYMZXCZXDKA-UHFFFAOYSA-N 0.000 description 1
- 229940124821 NNRTIs Drugs 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 102000013127 Vimentin Human genes 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 239000002487 adenosine deaminase inhibitor Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003127 anti-melanomic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940124691 antibody therapeutics Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- RYMCFYKJDVMSIR-RNFRBKRXSA-N apricitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)OC1 RYMCFYKJDVMSIR-RNFRBKRXSA-N 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 101150044616 araC gene Proteins 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- FEJQZESDPWHUIU-UHFFFAOYSA-N benzyl N-(2,2-dimethoxyethylsulfamoyl)carbamate Chemical compound COC(CNS(=O)(=O)NC(=O)OCc1ccccc1)OC FEJQZESDPWHUIU-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- NIDRYBLTWYFCFV-UHFFFAOYSA-N calanolide F Natural products C1=CC(C)(C)OC2=C1C(OC(C)C(C)C1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 1
- 230000004041 dendritic cell maturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 229950010030 dl-alanine Drugs 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- MLILORUFDVLTSP-UHFFFAOYSA-N emivirine Chemical compound O=C1NC(=O)N(COCC)C(CC=2C=CC=CC=2)=C1C(C)C MLILORUFDVLTSP-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000012054 flavored emulsion Substances 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 108010007811 human immunodeficiency virus p17 gag peptide Proteins 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000003259 immunoinhibitory effect Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000003046 intermediate neglect of differential overlap Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010212 intracellular staining Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 229950004697 lasinavir Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- KBEMFSMODRNJHE-JFWOZONXSA-N lodenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@@H]1F KBEMFSMODRNJHE-JFWOZONXSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- VELGMVLNORPMAO-JTFNWEOFSA-N n-[(e)-1-[(3r,4r,5s,6r)-5-[(2s,3r,4r,5r,6r)-5-[(2s,3r,4r,5r,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)-4-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxym Chemical compound O[C@@H]1[C@@H](O)C(OCC(NC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 VELGMVLNORPMAO-JTFNWEOFSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 229940042404 nucleoside and nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000002105 relative biological effectiveness Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000012764 semi-quantitative analysis Methods 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Abstract
Description
本出願は、4−({2−[(アミノスルホニル)アミノ]エチル}アミノ)−N−(3−ブロモ−4−フルオロフェニル)−N’−ヒドロキシ−1,2,5−オキサジアゾール−3−カルボキシミドアミド(癌及び他の障害の治療において有用なインドールアミン2,3−ジオキシゲナーゼの阻害剤)を作製するプロセス及び中間体に関する。
IDOは、子宮内での胎児拒絶を防止する免疫抑制性プロセスにおいて役割を果たすと考えられている。40年以上前に、組織移植免疫学によって予測されるものにもかかわらず、妊娠の間に、遺伝的に異なる哺乳類胚が生存することが観察された(非特許文献6)。母親と胎児の解剖学的な分離及び胎児の抗原性未熟では、胎児の同種異系移植片の生存について完全に説明することができない。最近の注目は、母親の免疫学的寛容に集中している。IDOがヒト合胞体栄養細胞層細胞によって発現され、全身的なトリプトファン濃度が正常妊娠の間に落ちるので、母親−胎児の境界でのIDO発現が胎児の同種異系移植片の免疫学的拒絶を防止するのに必要であるという仮説が立てられた。この仮説を検証するために、妊娠マウス(同系胎児または同種異系胎児を保有する)を1MTへ曝露し、すべての同種異系胚で急速なT細胞誘導性拒絶が観察された。したがって、トリプトファンの異化によって、哺乳類胎児はT細胞の活性を抑制して拒絶に対して防御し、マウス妊娠の間のトリプトファン異化作用のブロックは、母親のT細胞が胎児の同種異系移植片拒絶を誘発することを可能にすると思われる(非特許文献7)。
腫瘍に向けた免疫不応答に寄与する1つのメカニズムは、寛容原性の宿主APCによる腫瘍抗原の提示であり得る。CD123(IL3RA)及びCCR6を共発現し、T細胞増殖を阻害する、ヒトIDOを発現する抗原提示細胞(APC)のサブセットも記述されている。成熟及び未成熟の両方のCD123陽性樹状細胞はT細胞活性を抑制し、このIDO抑制活性は1MTによってブロックされた(非特許文献10)。マウス腫瘍灌流リンパ節(TDLN)が、免疫抑制性レベルのIDOを構成的に発現する形質細胞様樹状細胞(pDC)のサブセットを含有することも実証された。インビトロでリンパ節細胞の0.5%のみを構成するにもかかわらず、これらのpDCは、pDCそれ自体によって提示された抗原へのT細胞応答を強力に抑制し、非抑制性APCによって提示された第三者抗原へのT細胞応答も優性様式で抑制した。pDCの集団内で、大部分の機能的なIDO媒介性の抑制因子活性は、B系譜マーカーのCD19を共発現するpDCの新規のサブセットと共に分離された。したがって、TDLN中のpDCによるIDO媒介性の抑制は宿主の抗腫瘍性のT細胞応答を強力に抑制する局所的な微小環境を生成するという仮説が立てられた(非特許文献11)。
Pg2はアミノ保護基であり、
Xはハロである。
式中、
各々のR1は独立してアミノ保護基であり、
R3はC1−6アルキルまたはベンジルである。
式F14の化合物
式中、
R2はC1−4アルキルであり、
R3はC1−6アルキルまたはベンジルである。
式中、
各々のR1は独立してアミノ保護基であり、
R2はC1−4アルキルであり、
R3はC1−6アルキルまたはベンジルである。
式中、
R3はC1−6アルキルまたはベンジルであり
各々のR1は独立してアミノ保護基である。
式中、R3はC1−6アルキルまたはベンジルであり、各々のR1は独立してアミノ保護基である。
i)式F19の化合物
ii)式F20の該化合物を、式Iの化合物
を含むプロセスも提供する。いくつかの実施形態において、当該変換は、当該組み合わせ後に塩酸水溶液を添加することを更に含む。
式中、R4は、C1−6アルキル、C1−6ハロアルキルまたはベンジルである。
式中、R4は、C1−6アルキル、C1−6ハロアルキルまたはベンジルである。
式Iの化合物は、酵素インドールアミン−2,3−ジオキシゲナーゼ(IDO)の活性を阻害することができる。例えば、式Iの化合物は、細胞中の、または阻害量の式Iの化合物の投与による酵素の修飾を必要とする個体中のIDOの活性の阻害に使用することができる。
1つ以上の追加の医薬用薬剤または治療方法、例えば抗ウイルス薬剤、化学療法剤もしくは他の抗癌剤、免疫促進剤、免疫抑制薬、照射、抗腫瘍ワクチン及び抗ウイルスワクチン、サイトカイン療法(例えばIL2、GM−CSFなど)、及び/またはチロシンキナーゼ阻害剤等を、IDOに関連する疾患、障害または病態の治療のために式Iの化合物と組み合わせて使用することができる。薬剤は単一投薬量形状で式Iの化合物と組み合わせることができるか、または薬剤は分離した投薬量形状として同時にもしくは連続して投与することができる。
医薬品として用いられた場合に、式Iの化合物は医薬組成物の形状で投与することができ、それは式Iの化合物及び薬学的に許容される担体の組み合わせである。これらの組成物は医薬技術分野において周知の様式で調製することができ、局所的または全身的な治療が所望されるかどうか及び治療される領域に依存して、多様な経路によって投与することができる。投与は、局所(眼及び粘膜(鼻腔内、膣及び直腸の送達が含まれる)が含まれる)、肺(例えば粉末またはエアロゾルの吸入または通気(ネビュライザーが含まれる)によって;気管内、鼻腔内、表皮及び経皮)、眼、経口、または非経口であり得る。眼送達のための方法には、局所投与(点眼薬)、バルーン付きカテーテルによる結膜下、眼周囲もしく硝子体内の注射もしくは導入、または結膜嚢中に外科的に設置された眼用インサートが含まれ得る。非経口投与には、静脈内、動脈内、皮下、腹腔内、もしくは筋肉内の注射もしくは点滴;または頭蓋内、例えば髄腔内もしくは脳室内の投与が含まれる。非経口投与は単一ボーラス用量の形状であり得るか、または例えば継続的な灌流ポンプによるものであり得る。局所投与のための医薬組成物及び製剤には、経皮パッチ、軟膏、ローション、クリーム、ゲル、点滴薬、坐薬、スプレー、液体及び粉末が含まれ得る。従来の医薬用担体、水性、粉末または油性の基剤、増粘剤及び同種のものは、必要であるかまたは所望され得る。
500mLのフラスコへ、tert−ブチル[2−({4−[2−(3−ブロモ−4−フルオロフェニル)−5−オキソ−2,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル]−1,2,5−オキサジアゾール−3−イル}アミノ)エチル]カルバメート(20g、41.2mmol)及びイソプロパノール(255mL)を投入した。スラリーを室温で撹拌した。塩化水素ガス(7.55g、207mmol、5.0当量)を表面下のガラス管により16分間にわたってスラリーへ添加した。次いで酢酸エチル(111mL)をバッチへ添加し、反応を43℃へ加熱し、7.5時間撹拌した。バッチを19℃へ冷却し、酢酸エチル(44mL)を添加した。スラリーを濾過し、もたらされた残渣を酢酸エチル(2×55mL)により洗浄した。単離した固体を減圧下で45℃で15時間乾燥して、オフホワイトから白色の固体として所望される産物(16.61g、95.5%の収率)を得た。1H NMR (300 MHz, DMSO−d6) δ 8.11 (bs, 3H), 7.78 (m, 1H), 7.73 (m, 1H), 7.59 (t, 1H, J = 8.7 Hz), 6.74 (t, 1H, J = 6.1 Hz), 3.50 (m, 2H), 3.02 (m, 2H); C12H11BrClFN6O3, (分子量421.61;遊離塩基のC12H10BrFN6O3、分子量385.15), LCMS (EI) m/e 385/387 (M+ + H).
トリアセトキシ水素化ホウ素ナトリウム(2.33g、11.0mmol、11.0当量)をトリフルオロ酢酸(12.0mL、155.8mmol、155.8当量)と混合した。もたらされた溶液を室温で30分間混合した。ジクロロメタン(10.0mL)及びアセトニトリル(6.0mL)中の3−(4−アミノ−1,2,5−オキサジアゾール−3−イル)−4−(3−ブロモ−4−フルオロフェニル)−1,2,4−オキサジアゾール−5(4H)−オン(5、0.342g、1.0mmol)及びtert−ブチル(2−オキソエチル)カルバメート(Sigma−Aldrich)(1.04g、6.51mmol、6.5当量)の溶液を、N2下で撹拌した。この溶液を−5℃へ冷却し、トリアセトキシ水素化ホウ素ナトリウム及びトリフルオロ酢酸の溶液を5分間にわたって滴加した。反応を室温で4時間撹拌した。HPLC及びLC−MS(M+−Boc+H:385/387、臭化物パターン)は、所望される産物と出発材料の比が4対1であることを示した。混合物を濃縮し、ジクロロメタン(10mL)により希釈した。溶液を0℃へ冷却し、4Nの水酸化ナトリウムを0〜5℃の温度を維持しながらゆっくり添加して、pHを8〜9へ調整した。水層をジクロロメタン(3×10mL)により抽出した。合わせたジクロロメタン溶液を重炭酸ナトリウム及びブラインにより洗浄し、硫酸ナトリウムの上で乾燥し、濃縮した。次いで粗製残渣をジクロロメタン(6.0mL)中で溶解し、もたらされた溶液を0℃へ冷却した。ジオキサン(3.0mL)中の4Nの塩酸を0〜5℃で滴加した。混合物を室温で20分間撹拌した。濾過によって沈殿物を収集し、ジエチルエーテルにより洗浄し、真空中で乾燥して、オフホワイト固体として所望される産物(289mg、54%)を得た。1H NMR (300 MHz, DMSO−d6) δ 8.11 (bs, 3H), 7.78 (m, 1H), 7.73 (m, 1H), 7.59 (t, 1H, J = 8.7 Hz), 6.74 (t, 1H, J = 6.1 Hz), 3.50 (m, 2H), 3.02 (m, 2H); C12H11BrClFN6O3, (分子量421.61;遊離塩基でC12H10BrFN6O3 、分子量385.15), LCMS (EI) m/e 385/387 (M+ + H).
5Lの丸底フラスコに、tert−ブタノール(253g、3.41mol、1.2当量)及びジクロロメタン(2.6L)を投入した。溶液を0.9℃へ冷却した。この溶液へ、クロロスルホニルイソシアネート(463g、3.27mol、1.15当量)を、10℃未満のバッチ温度を維持しながら43分間にわたって添加した。もたらされたtert−ブチル(クロロスルホニル)カルバメート溶液を3〜5℃で1時間保持した。
ステップ2b。ベンジル({[2−({[4−(3−ブロモ−4−フルオロフェニル)−5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル]−1,2,5−オキサジアゾール−3−イル}アミノ)エチル]アミノ}スルホニル)カルバメート(18b)
N末端のHisタグを備えたヒトインドールアミン2,3−ジオキシゲナーゼ(IDO)を大腸菌中で発現させ、均一になるまで精製した。IDOは、トリプトファンのインドール核のピロール環の酸化的開裂を触媒して、N’−ホルミルキヌレニンをもたらす。アッセイは、50mMのリン酸カリウム緩衝液(pH6.5)中の20mMのアスコルビン酸塩、5μMのメチレンブルー及び0.2mg/mLのカタラーゼの存在下において、95nMのIDO及び2mMのD−Trpを使用して、文献中で記述されるように室温で遂行した。最初の反応速度、続いてN’−ホルミルキヌレニンの形成に起因する321nmでの吸収増加を連続的に記録した(Sono,M.,et al.,1980,J.Biol.Chem.255,1339−1345を参照)。式Iの化合物を実施例Aのアッセイにおいて試験し、200nM未満のIC50を有することが見出された。
HeLa細胞(#CCL−2)をAmerican Type Tissue Culture Collection(ATCC、Manassas、VA)から入手し、1.5g/Lの重炭酸ナトリウム、0.1mMの非必須アミノ酸、1mMのピルビン酸ナトリウム及び10%のウシ胎仔血清(すべてInvitrogenから)を含有するように調整した、2mMのL−グルタミン及びEarleのBSSを含有する最小必須培地(Eagle)中で通常法で維持した。細胞を、5%のCO2を供給した加湿インキュベーター中で37℃で維持した。アッセイを以下の通り遂行した。HeLa細胞を1ウェルあたり5×103の密度で96ウェル培養プレート中で播種し、一晩増殖させた。翌日に、IFN−γ(50ng/mLの最終濃度)及び化合物の連続希釈物(200μLの培養培地の全体積で)を、細胞の中へ添加した。48時間のインキュベーション後に、1ウェルあたり140μLの上清を新しい96ウェルプレートへ移した。10μLの6.1Nのトリクロロ酢酸(#T0699、Sigma)を各々のウェルの中へ混合し、50℃で30分間インキュベーションして、インドールアミン2,3−ジオキシゲナーゼによって産生されたN−ホルミルキヌレニンをキヌレニンへ加水分解した。次いで反応混合物を2500rpmで10分間遠心分離して沈殿物を除去した。1ウェルあたり100μLの上清を別の96ウェルプレートへ移し、100μlの酢酸中の2%(w/v)のp−ジメチルアミノベンズアルデヒド(#15647−7、Sigma−Aldrich)と混合した。キヌレニンに由来する黄色を、SPECTRAmax 250マイクロプレートリーダー(Molecular Devices)を使用して480nmで測定した。L−キヌレニン(#K8625、Sigma)を標準として使用した。標準(240、120、60、30、15、7.5、3.75、1.87μM)を、100μLの培養培地中で調製し、等体積の2%(w/v)のp−ジメチルアミノベンズアルデヒドと混合した。個別の濃度で阻害パーセントを決定し、二重で平均値を得た。データを非直線回帰の使用によって分析して、IC50値(Prism Graphpad)を生成した。Takikawa O,et al.,1988,J.Biol.Chem.,263(4):2041−8を参照されたい。
単球を白血球泳動(leukophoresis)によってヒト末梢単核球から集めた。次いで単球を、10%のウシ胎仔血清及び2mMのL−グルタミン(すべてInvitrogenから)を補足したRPMI 1640培地を使用して、96ウェルプレート中に1×106細胞/ウェルの密度で播種した。37℃で一晩の培養後に、接着細胞をプレート上で保持した。次いで接着単球を、100ng/mlのGM−CSF(#300−03、PeproTech)及び250ng/mlのIL−4(#200−04、PeproTech)により5〜7日間刺激し、続いて5μg/mLのSalmonella typhimuriumからのLPS(#437650、Sigma)及び50ng/mLのIFN−γ(#285−IF、R&D Systems)により追加の2日間活性化して、樹状細胞の成熟を誘導した。
インビボの抗腫瘍有効性は、改変した腫瘍同種異系移植/異種移植プロトコルを使用して試験することができる。例えば、IDO阻害が、免疫能のあるマウスにおいて細胞傷害性化学療法と相乗できることが文献中で記述されている(Muller,A.J.,et al.2005,Nat.Med.11:312−319)。この相乗性がT細胞に依存するということは、免疫能のあるシンジェニックマウスにおいて増殖させたマウス腫瘍の異種移植モデル(例えばB16及び関連バリアント、CT−26、LLC)における調査中のIDO阻害剤の相乗効果を、抗CD4中和抗体により処理されたシンジェニックマウスにおいて観察されたもの、または免疫力が低下したマウス(例えばnu/nu)において増殖された同じ腫瘍に比較することによって示された。
1.細胞単離及びウイルス感染
単球及びPBLを、白血球泳動(leukopheresis)パックの向流遠心分離式溶出によって、HIV−1、2及びB型肝炎の血清陰性のドナーから得ることができる。単球は、10%の非動化したプールヒト血清、1%のグルタミン、50μg/mLのゲンタマイシン、10μg/mLのシプロフロキサシン(Sigma)及び1000U/mLの高度に精製された組換えヒトマクロファージコロニー刺激因子を補足したDulbecco改変Eagle培地(DMEM、Sigma−Aldrich)中で、テフロンフラスコを使用して浮遊培養で培養する。培養7日後に、単球由来マクロファージ(MDM)を0.01の感染多重度でHIV−1ADAに感染させる。
4週齢の雄NOD/C.B−17 SCIDマウスを購入することができる(Jackson Laboratory)。動物を病原体不含有条件下の滅菌マイクロアイソレーターケージ中で維持する。すべての動物に、PBL移植の3日前にラット抗CD122(0.25mg/マウス)、ならびにPBL注射(20×106細胞/マウス)の1日前及び3日後にウサギアシアロ−GM1抗体(0.2mg/マウス)(Wako)の2回を腹腔内注射する。HIV−1ADAに感染させたMDM(10μL中で3×105細胞)をPBL再構成の8日後に頭蓋内(i.c.)注射し、hu−PBL−NOD/SCID HIVEマウスを生成する。HIV−1に感染させたMDMのi.c.注射の直後に、hu−PBL−NOD/SCID HIVEマウスに、対照(ベヒクル)または化合物ペレット(14日または28日の遅延放出、Innovative Research)を皮下(s.c)移植する。初期実験は、IDO化合物により処理されたhu PBL−NOD/SCID HIVE動物におけるウイルス特異的なCTLの誘導を確認するように設計される。これは、四量体染色、及び脳組織からのMDM排除の神経病理学的解析によって確認される。次いで、実験は、ヒトリンパ球再構成、体液性免疫反応及び神経病理学的変性を分析するように設計される。これらの実験において、7日目に動物から採血し、ヒトMDMのi.c.注射後14及び21日目に屠殺する。EDTA含有チューブ中に収集した血液をフローサイトメトリーのために使用し、血漿を、ELISAを使用するHIV−1 p24の検出のために使用する(Beckman Coulter(商標))。HIV−1特異的抗体は、製造業者説明書(Cambridge Biotech HIV−1ウエスタンブロットキット、Calypte Biomedical)に従ってウエスタンブロット試験によって検出される。類似の量のウイルス特異的な抗体が、対照動物及び化合物処理動物で検出される。合計3つの独立した実験を、3つの異なるヒト白血球ドナーを使用して遂行することができる。
2色FACS分析を、ヒトMDMのi.c.注射後1〜3週目に末梢血ならびに2及び3週目に脾細胞で遂行することができる。細胞を、ヒトCD4、CD8、CD56、CD3、IFN−γ(eBioscience)に対する蛍光色素コンジュゲートモノクローナル抗体(mAb)により4℃で30分間インキュベーションする。細胞性免疫応答を評価するために、IFN−γ細胞内染色を抗ヒトCD8及びFITCコンジュゲート抗マウスCD45と組み合わせて遂行して、マウス細胞を除外する。抗原に特異的なCTLを決定するために、HIV1gag(p17(アミノ酸77〜85)SLYNTVATL、SL−9)及びHIV−1pol[(アミノ酸476〜485)ILKEPVHGV、IL−9]についてのアロフィコシアニンコンジュゲート四量体染色を、赤血球凝集素/インターロイキン2(PHA/IL−2)刺激脾細胞で遂行する。NIH/National Institute of Allergy and Infections Disease、National Tetramer Core Facilitiesの推奨に従って、細胞を染色する。CellQuestソフトウェア(Becton Dickinson Immunocytometry System)を使用してFACS Calibur(商標)によりデータを分析した。
脳組織をMDMのi.c.注射後14及び21日目に収集し、4%のリン酸緩衝パラホルムアルデヒド中で固定し、パラフィン中に包埋するか、または後の使用のために−80℃で凍結する。包埋したブロックからの冠状断片を、注射部位を特定するために切断する。各々のマウスについて、30〜100枚(5μm厚)の連続切片をヒトMDM注射部位から切断し、3〜7枚のスライド(10切片分離れて)を分析する。脳切片をキシレンにより脱パラフィンし、アルコール勾配中で水和する。免疫組織化学的染色は、抗原性回復のための0.01mol/Lのクエン酸緩衝液中の95℃への30分間の加熱による抗原性回復を使用する、基本的な間接プロトコルに従う。マウス脳中でヒト細胞を特定するために、すべてのヒト白血球を特定するビメンチンに対するmAb(1:50、クローン3B4、Dako Corporation)を使用する。ヒトMDM及びCD8+リンパ細胞を、CD68(1:50希釈、クローンKP1)及びCD8(1:50希釈、クローン144B)抗体によりそれぞれ検出する。ウイルス感染細胞を、HIV−1 p24に対するmAb(1:10、クローンKal−1、すべてDakoから)により標識する。反応性のマウス小グリア細胞をIba−1抗体(1:500、Wako)により検出する。ヒトIDO(huIDO)の発現を、Department of Cell Pharmacology、Central Research Institute、Graduate School of Medicine, Hokkaido University、Sapporo、日本国から得たAbにより可視化する。一次抗体を適切なビオチン化二次抗体により検出し、アビジン−ビオチン複合体(Vectastain Elite ABCキット、Vector Laboratories)及びホースラディシュペルオキシダーゼ(HRP)をカップルしたデキストランポリマー(EnVision、Dako Corporation)により可視化する。免疫染色された切片をMayerのヘマトキシリンにより対比染色する。一次抗体を欠失した切片または無関係のIgGアイソタイプを取り込んだ切片を対照として供した。独立した2人の観察者が、盲検化様式で、各々のマウスからの各々の切片中のCD8+リンパ細胞、CD68+MDM及びHIV−1 p24+細胞の数を計数する。光学顕微鏡検査はNikon Eclipse 800顕微鏡(Nikon Instruments Inc)により遂行される。Iba1についての半定量分析(免疫染色によって占められる面積のパーセンテージ)を、コンピューター支援画像分析(Image−Pro(登録商標)Plus、Media Cybernetics)によって、従来記述されるように実行する。
データは、比較のためのStudentのt検定及びANOVAによりPrism(Graph Pad)を使用して分析することができる。0.05未満のP値を有意とみなした。
Poluektova LY,Munn DH,Persidsky Y,and Gendelman HE(2002).Generation of cytotoxic T cells against virus−infected human brain macrophages in a murine model of HIV−1 encephalitis.J.Immunol.168(8):3941−9.
500mLのフラスコへ、tert−ブチル[2−({4−[4−(3−ブロモ−4−フルオロフェニル)−5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル]−1,2,5−オキサジアゾール−3−イル}アミノ)エチル]カルバメート(20g、41.2mmol)及びイソプロパノール(255mL)を投入した。スラリーを室温で撹拌した。塩化水素ガス(7.55g、207mmol、5.0当量)を表面下のガラス管により16分間にわたってスラリーへ添加した。次いで酢酸エチル(111mL)をバッチへ添加し、反応を43℃へ加熱し、7.5時間撹拌した。バッチを19℃へ冷却し、酢酸エチル(44mL)を添加した。スラリーを濾過し、もたらされた残渣を酢酸エチル(2×55mL)により洗浄した。単離した固体を減圧下で45℃で15時間乾燥して、オフホワイトから白色の固体として所望される産物(16.61g、95.5%の収率)を得た。1H NMR (300 MHz, DMSO−d6) δ 8.11 (bs, 3H), 7.78 (m, 1H), 7.73 (m, 1H), 7.59 (t, 1H, J = 8.7 Hz), 6.74 (t, 1H, J = 6.1 Hz), 3.50 (m, 2H), 3.02 (m, 2H); C12H11BrClFN6O3, (分子量421.61;遊離塩基のC12H10BrFN6O3、分子量385.15), LCMS (EI) m/e 385/387 (M+ + H).
[発明1]
式F5の化合物
[発明2]
Pg 1 が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項1に記載のプロセス。
[発明3]
Pg 1 がtert−ブトキシカルボニルである、請求項1に記載のプロセス。
[発明4]
前記反応が還元剤の存在下において遂行される、請求項1〜3のいずれか一項に記載のプロセス。
[発明5]
前記還元剤が水素化ホウ素還元剤である、請求項4に記載のプロセス。
[発明6]
前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項5に記載のプロセス。
[発明7]
前記式F7の化合物を脱保護して、式F8の化合物
[発明8]
前記脱保護が式F7の化合物を塩酸と反応させることを含む、請求項7に記載のプロセス。
[発明9]
前記式F8の化合物を、有機塩基の存在下においてPg 2 −NH−SO 2 −Xと反応させて、式F9の化合物
式中、
Pg 2 はアミノ保護基であり、
Xはハロである、
請求項7または8のいずれか一項に記載のプロセス。
[発明10]
Pg 2 が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項9に記載のプロセス。
[発明11]
Pg 2 がtert−ブトキシカルボニルである、請求項9に記載のプロセス。
[発明12]
Xがクロロである、請求項9〜11のいずれか一項に記載のプロセス。
[発明13]
前記式F9の化合物を脱保護して、式F10の化合物
[発明14]
前記脱保護が式F9の化合物を塩酸と反応させることを含む、請求項13に記載のプロセス。
[発明15]
前記脱保護が、式F9の化合物を酢酸エチルを含む溶媒構成要素中で塩酸と反応させることを含む、請求項13に記載のプロセス。
[発明16]
前記式F10の化合物を塩基と反応させて、式Iの化合物
[発明17]
前記塩基が水酸化ナトリウムである、請求項16に記載のプロセス。
[発明18]
式F15の化合物
式中、
各々のR 1 は独立してアミノ保護基であり、
R 3 はC 1−6 アルキルまたはベンジルである、プロセス。
[発明19]
各々のR 1 が、C 2−4 アルケニル−C 1−3 アルキルまたはフェニル−C 1−3 アルキルであり、前記フェニル−C 1−3 アルキルが、1、2または3の独立して選択されるC 1−4 アルコキシ基によって随意に置換される、請求項18に記載のプロセス。
[発明20]
各々のR 1 がアリルである、請求項18に記載のプロセス。
[発明21]
各々のR 1 が4−メトキシベンジルである、請求項18に記載のプロセス。
[発明22]
R 3 がC 1−6 アルキルである、請求項18に記載のプロセス。
[発明23]
R 3 がtert−ブチルである、請求項18に記載のプロセス。
[発明24]
前記反応が還元剤の存在下において遂行される、請求項18〜23のいずれか一項に記載のプロセス。
[発明25]
前記還元剤が水素化ホウ素還元剤である、請求項24に記載のプロセス。
[発明26]
前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項25に記載のプロセス。
[発明27]
前記反応がトリフルオロ酢酸の存在下において遂行される、請求項24〜26のいずれか一項に記載のプロセス。
[発明28]
前記式F16の化合物を脱保護して、式F10の化合物
[発明29]
前記脱保護が式F16の化合物をトリフルオロ酢酸と反応させることを含む、請求項28に記載のプロセス。
[発明30]
前記脱保護が式F16の化合物を塩酸と反応させることを含む、請求項28に記載のプロセス。
[発明31]
式F15の前記化合物が、式F14の化合物
[発明32]
前記還元剤が水素化ジイソブチルアルミニウムである、請求項31に記載のプロセス。
[発明33]
前記式F14の化合物が、式F13の化合物
[発明34]
前記1つ以上のアミノ保護剤が、臭化アリル及び4−メトキシベンジルクロライドから選択される、請求項33に記載のプロセス。
[発明35]
前記保護が塩基の存在下において遂行される、請求項33または34のいずれか一項に記載のプロセス。
[発明36]
式F15の化合物
R 3 はC 1−6 アルキルまたはベンジルであり、
各々のR 1 は独立してアミノ保護基である)。
[発明37]
tert−ブチルアリル{[アリル(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
[発明38]
tert−ブチル(4−メトキシベンジル){[(4−メトキシベンジル)(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
[発明39]
式F17の化合物
[発明40]
R 4 がtert−ブチルである、請求項39に記載のプロセス。
[発明41]
R 4 がベンジルである、請求項39に記載のプロセス。
[発明42]
R 4 がエチルである、請求項39に記載のプロセス。
[発明43]
R 4 が2,2,2−トリクロロエチルである、請求項39に記載のプロセス。
[発明44]
前記反応が還元剤の存在下において実行される、請求項40〜43のいずれか一項に記載のプロセス。
[発明45]
前記還元剤がトリエチルシランである、請求項44に記載のプロセス。
[発明46]
前記反応が有機酸の存在下において実行される、請求項44または45のいずれか一項に記載のプロセス。
[発明47]
前記有機酸がトリフルオロ酢酸である、請求項46に記載のプロセス。
[発明48]
前記式F18の化合物を脱保護して、式F10の化合物
[発明49]
前記脱保護が、式F18の化合物を酢酸の存在下において亜鉛と反応させることを含む、請求項48に記載のプロセス。
[発明50]
式F10の前記化合物を塩基と反応させて、式Iの化合物
[発明51]
前記塩基が水酸化ナトリウムである、請求項50に記載のプロセス。
[発明52]
R 4 が9H−フルオレン−9−イルメチルである、請求項39に記載のプロセス。
[発明53]
前記反応が還元剤の存在下において実行される、請求項52に記載のプロセス。
[発明54]
前記還元剤がトリエチルシランである、請求項53に記載のプロセス。
[発明55]
前記反応が有機酸の存在下において実行される、請求項53または54のいずれか一項に記載のプロセス。
[発明56]
前記有機酸がメタンスルホン酸である、請求項55に記載のプロセス。
[発明57]
前記式F18の化合物を、式Iの化合物
[発明58]
前記塩基がN,N−ビス(2−アミノエチル)エタン−1,2−ジアミンである、請求項57に記載のプロセス。
[発明59]
前記変換が塩酸水溶液を前記第1の混合物へ添加することを更に含む、請求項57〜58のいずれか一項に記載のプロセス。
[発明60]
式F17の化合物
[発明61]
tert−ブチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明62]
ベンジルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明63]
エチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明64]
2,2,2−トリクロロエチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明65]
(9H−フルオレン−9−イル)メチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明66]
i)式F19の化合物
ii)前記式F20の化合物を、式Iの化合物
を含む、プロセス。
本発明の様々な改変形態が、本明細書において記述されたものに加えて、前述の記述から当業者には明らかであろう。かかる改変形態も添付の請求項の範囲内であることが意図される。すべての特許、特許出願及び出版物を含む、本出願中で引用される各々の参考文献は、それらの全体が参照によって本明細書に援用される。
Claims (66)
- 式F5の化合物
- Pg1が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項1に記載のプロセス。
- Pg1がtert−ブトキシカルボニルである、請求項1に記載のプロセス。
- 前記反応が還元剤の存在下において遂行される、請求項1〜3のいずれか一項に記載のプロセス。
- 前記還元剤が水素化ホウ素還元剤である、請求項4に記載のプロセス。
- 前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項5に記載のプロセス。
- 前記式F7の化合物を脱保護して、式F8の化合物
- 前記脱保護が式F7の化合物を塩酸と反応させることを含む、請求項7に記載のプロセス。
- 前記式F8の化合物を、有機塩基の存在下においてPg2−NH−SO2−Xと反応させて、式F9の化合物
式中、
Pg2はアミノ保護基であり、
Xはハロである、
請求項7または8のいずれか一項に記載のプロセス。 - Pg2が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項9に記載のプロセス。
- Pg2がtert−ブトキシカルボニルである、請求項9に記載のプロセス。
- Xがクロロである、請求項9〜11のいずれか一項に記載のプロセス。
- 前記式F9の化合物を脱保護して、式F10の化合物
- 前記脱保護が式F9の化合物を塩酸と反応させることを含む、請求項13に記載のプロセス。
- 前記脱保護が、式F9の化合物を酢酸エチルを含む溶媒構成要素中で塩酸と反応させることを含む、請求項13に記載のプロセス。
- 前記式F10の化合物を塩基と反応させて、式Iの化合物
- 前記塩基が水酸化ナトリウムである、請求項16に記載のプロセス。
- 式F15の化合物
式中、
各々のR1は独立してアミノ保護基であり、
R3はC1−6アルキルまたはベンジルである、プロセス。 - 各々のR1が、C2−4アルケニル−C1−3アルキルまたはフェニル−C1−3アルキルであり、前記フェニル−C1−3アルキルが、1、2または3の独立して選択されるC1−4アルコキシ基によって随意に置換される、請求項18に記載のプロセス。
- 各々のR1がアリルである、請求項18に記載のプロセス。
- 各々のR1が4−メトキシベンジルである、請求項18に記載のプロセス。
- R3がC1−6アルキルである、請求項18に記載のプロセス。
- R3がtert−ブチルである、請求項18に記載のプロセス。
- 前記反応が還元剤の存在下において遂行される、請求項18〜23のいずれか一項に記載のプロセス。
- 前記還元剤が水素化ホウ素還元剤である、請求項24に記載のプロセス。
- 前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項25に記載のプロセス。
- 前記反応がトリフルオロ酢酸の存在下において遂行される、請求項24〜26のいずれか一項に記載のプロセス。
- 前記式F16の化合物を脱保護して、式F10の化合物
- 前記脱保護が式F16の化合物をトリフルオロ酢酸と反応させることを含む、請求項28に記載のプロセス。
- 前記脱保護が式F16の化合物を塩酸と反応させることを含む、請求項28に記載のプロセス。
- 式F15の前記化合物が、式F14の化合物
- 前記還元剤が水素化ジイソブチルアルミニウムである、請求項31に記載のプロセス。
- 前記式F14の化合物が、式F13の化合物
- 前記1つ以上のアミノ保護剤が、臭化アリル及び4−メトキシベンジルクロライドから選択される、請求項33に記載のプロセス。
- 前記保護が塩基の存在下において遂行される、請求項33または34のいずれか一項に記載のプロセス。
- 式F15の化合物
R3はC1−6アルキルまたはベンジルであり、
各々のR1は独立してアミノ保護基である)。 - tert−ブチルアリル{[アリル(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
- tert−ブチル(4−メトキシベンジル){[(4−メトキシベンジル)(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
- 式F17の化合物
- R4がtert−ブチルである、請求項39に記載のプロセス。
- R4がベンジルである、請求項39に記載のプロセス。
- R4がエチルである、請求項39に記載のプロセス。
- R4が2,2,2−トリクロロエチルである、請求項39に記載のプロセス。
- 前記反応が還元剤の存在下において実行される、請求項40〜43のいずれか一項に記載のプロセス。
- 前記還元剤がトリエチルシランである、請求項44に記載のプロセス。
- 前記反応が有機酸の存在下において実行される、請求項44または45のいずれか一項に記載のプロセス。
- 前記有機酸がトリフルオロ酢酸である、請求項46に記載のプロセス。
- 前記式F18の化合物を脱保護して、式F10の化合物
- 前記脱保護が、式F18の化合物を酢酸の存在下において亜鉛と反応させることを含む、請求項48に記載のプロセス。
- 式F10の前記化合物を塩基と反応させて、式Iの化合物
- 前記塩基が水酸化ナトリウムである、請求項50に記載のプロセス。
- R4が9H−フルオレン−9−イルメチルである、請求項39に記載のプロセス。
- 前記反応が還元剤の存在下において実行される、請求項52に記載のプロセス。
- 前記還元剤がトリエチルシランである、請求項53に記載のプロセス。
- 前記反応が有機酸の存在下において実行される、請求項53または54のいずれか一項に記載のプロセス。
- 前記有機酸がメタンスルホン酸である、請求項55に記載のプロセス。
- 前記式F18の化合物を、式Iの化合物
- 前記塩基がN,N−ビス(2−アミノエチル)エタン−1,2−ジアミンである、請求項57に記載のプロセス。
- 前記変換が塩酸水溶液を前記第1の混合物へ添加することを更に含む、請求項57〜58のいずれか一項に記載のプロセス。
- 式F17の化合物
- tert−ブチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
- ベンジルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
- エチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
- 2,2,2−トリクロロエチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
- (9H−フルオレン−9−イル)メチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
- i)式F19の化合物
ii)前記式F20の化合物を、式Iの化合物
を含む、プロセス。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361901689P | 2013-11-08 | 2013-11-08 | |
US61/901,689 | 2013-11-08 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018187218A Division JP6633163B2 (ja) | 2013-11-08 | 2018-10-02 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020019806A true JP2020019806A (ja) | 2020-02-06 |
JP6883079B2 JP6883079B2 (ja) | 2021-06-09 |
Family
ID=52023608
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016528055A Active JP6461953B2 (ja) | 2013-11-08 | 2014-11-07 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
JP2018187218A Active JP6633163B2 (ja) | 2013-11-08 | 2018-10-02 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
JP2019184589A Active JP6883079B2 (ja) | 2013-11-08 | 2019-10-07 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
JP2019184577A Active JP6913725B2 (ja) | 2013-11-08 | 2019-10-07 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016528055A Active JP6461953B2 (ja) | 2013-11-08 | 2014-11-07 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
JP2018187218A Active JP6633163B2 (ja) | 2013-11-08 | 2018-10-02 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019184577A Active JP6913725B2 (ja) | 2013-11-08 | 2019-10-07 | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス |
Country Status (31)
Country | Link |
---|---|
US (3) | US9321755B2 (ja) |
EP (2) | EP3066085B1 (ja) |
JP (4) | JP6461953B2 (ja) |
KR (2) | KR102617531B1 (ja) |
CN (2) | CN109810104B (ja) |
AR (1) | AR098343A1 (ja) |
AU (2) | AU2014346647B2 (ja) |
BR (2) | BR112016009786B1 (ja) |
CA (1) | CA2929552C (ja) |
CL (1) | CL2016001082A1 (ja) |
CR (2) | CR20160252A (ja) |
CY (1) | CY1123164T1 (ja) |
DK (1) | DK3066085T3 (ja) |
EA (2) | EA033667B1 (ja) |
ES (1) | ES2799582T3 (ja) |
HR (1) | HRP20201089T1 (ja) |
HU (1) | HUE049337T2 (ja) |
IL (2) | IL245314B (ja) |
LT (1) | LT3066085T (ja) |
ME (1) | ME03792B (ja) |
MX (2) | MX366874B (ja) |
MY (1) | MY174254A (ja) |
PE (2) | PE20220430A1 (ja) |
PH (2) | PH12016500818A1 (ja) |
PL (1) | PL3066085T3 (ja) |
PT (1) | PT3066085T (ja) |
RS (1) | RS60598B1 (ja) |
SG (2) | SG11201603433UA (ja) |
SI (1) | SI3066085T1 (ja) |
TW (3) | TWI651311B (ja) |
WO (1) | WO2015070007A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112341403A (zh) * | 2020-11-10 | 2021-02-09 | 南京工业大学 | 一种利用微流场反应技术制备3-氨基-4-偕胺肟基呋咱的方法 |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1879573T3 (pl) | 2005-05-10 | 2013-05-31 | Incyte Holdings Corp | Modulatory 2,3-dioksygenazy indoloaminy i sposoby ich zastosowania |
EP2824100B1 (en) | 2008-07-08 | 2018-02-21 | Incyte Holdings Corporation | 1,2,5-Oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase |
GB201311891D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compound |
GB201311888D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
AR098343A1 (es) | 2013-11-08 | 2016-05-26 | Incyte Holdings Corp | Proceso para la síntesis de un inhibidor de indolamina 2,3-dioxigenasa |
MX2016010080A (es) * | 2014-02-04 | 2016-10-07 | Incyte Corp | Combinacion de un antagonista de muerte programada-1 y un inhibidor de indolamina 2,3-dioxigenasa 1 para el tratamiento del cancer. |
WO2017010106A1 (en) * | 2015-07-14 | 2017-01-19 | Kyowa Hakko Kirin Co., Ltd. | A therapeutic agent for a tumor comprising an ido inhibitor administered in combination with an antibody |
MA43172A (fr) | 2015-11-04 | 2018-09-12 | Incyte Corp | Compositions pharmaceutiques et méthodes d'inhibition d'indolamine 2,3-dioxygénase et leurs indications |
EP3389783B1 (en) * | 2015-12-15 | 2024-07-03 | Merck Sharp & Dohme LLC | Novel compounds as indoleamine 2,3-dioxygenase inhibitors |
US9624185B1 (en) * | 2016-01-20 | 2017-04-18 | Yong Xu | Method for preparing IDO inhibitor epacadostat |
CN105646389B (zh) * | 2016-01-28 | 2019-06-28 | 中国科学院上海有机化学研究所 | 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途 |
WO2017181849A1 (zh) * | 2016-04-20 | 2017-10-26 | 江苏豪森药业集团有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
CN107304191B (zh) * | 2016-04-20 | 2023-09-29 | 上海翰森生物医药科技有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
EP3505517A4 (en) | 2016-08-23 | 2020-01-15 | Beijing InnoCare Pharma Tech Co., Ltd. | FUSED HETEROCYCLIC DERIVATIVE, ITS PREPARATION METHOD AND ITS MEDICAL USE |
WO2018054365A1 (en) | 2016-09-24 | 2018-03-29 | Beigene, Ltd. | NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES |
EP3544965A4 (en) * | 2016-11-28 | 2020-05-20 | Shanghai Fochon Pharmaceutical Co., Ltd. | SULFOXIMIN, SULFONIMIDAMID, SULFONDIIMIN AND DIIMIDOSULFONAMID COMPOUNDS AS INHIBITORS OF INDOLAMINE-2,3-DIOXYGENASE |
CN110382508B (zh) | 2016-12-22 | 2022-08-02 | 卡里塞拉生物科学股份公司 | 用于抑制精氨酸酶活性的组合物和方法 |
CN109206380A (zh) * | 2017-07-03 | 2019-01-15 | 上海时莱生物技术有限公司 | 吲哚胺2,3-双加氧酶抑制剂化合物及其制备方法和用途 |
CN110066253B (zh) * | 2018-01-24 | 2023-06-23 | 江苏柯菲平医药股份有限公司 | 1,2,5-噁二唑类衍生物,其制备方法及其在医药中的应用 |
CN108101899B (zh) * | 2018-02-11 | 2021-01-26 | 中国药科大学 | IDO1抑制剂Epacadostat中间体的制备方法 |
CN109180603A (zh) * | 2018-10-10 | 2019-01-11 | 中国药科大学 | Epacadostat关键中间体的制备方法 |
MX2022001133A (es) | 2019-08-01 | 2022-04-25 | Incyte Corp | Regimen de dosificacion para un inhibidor de indolamina 2,3-dioxigenasa (ido). |
US20220409581A1 (en) * | 2019-11-14 | 2022-12-29 | Nova Southeastern University | Methods and compositions for treatment of solid tumors using f16 isoindole small molecules |
BR112023017582A2 (pt) | 2021-03-05 | 2023-12-05 | Univ Basel | Composições para o tratamento de doenças ou condições associadas ao ebv |
EP4052705A1 (en) | 2021-03-05 | 2022-09-07 | Universität Basel Vizerektorat Forschung | Compositions for the treatment of ebv associated diseases or conditions |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040138448A1 (en) * | 2002-10-12 | 2004-07-15 | The Scripps Research Institute | Synthesis of non-symmetrical sulfamides using burgess-type reagents |
JP2011527686A (ja) * | 2008-07-08 | 2011-11-04 | インサイト・コーポレイション | インドールアミン2,3−ジオキシゲナーゼの阻害剤としての1,2,5−オキサジアゾール |
Family Cites Families (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3236855A (en) | 1964-01-17 | 1966-02-22 | Merck & Co Inc | Certain n-phenyl(thiazole-hydroxamidine) compounds and their preparation |
US3354174A (en) | 1964-02-19 | 1967-11-21 | Sterling Drug Inc | 1-and 2-benzimidazolyl-lower-alkylamidoximes, amidines-, and guanidines |
US3553228A (en) | 1967-09-26 | 1971-01-05 | Colgate Palmolive Co | 3-substituted-4h(1)benzopyrano(3,4-d) isoxazoles |
DE2040628A1 (de) | 1970-08-17 | 1972-02-24 | Fahlberg List Veb | Neue herbizide Mittel |
US3948928A (en) | 1972-03-17 | 1976-04-06 | Dainippon Pharmaceutical Co., Ltd. | 3-Substituted-1,2-benzisoxazoles and pharmaceutically acceptable acid addition salts thereof |
JPS5621033B2 (ja) | 1973-09-05 | 1981-05-16 | ||
DD128918A5 (de) | 1975-09-11 | 1977-12-21 | Philagro Sa | Phythohormonale und herbizide zusammensetzungen |
FR2323683A1 (fr) | 1975-09-11 | 1977-04-08 | Philagro Sa | Nouveaux derives d'amidoximes, leur preparation et les compositions qui les contiennent |
US4323681A (en) | 1980-09-29 | 1982-04-06 | American Home Products Corporation | 4-Amino-2-substituted-5-pyrimidinecarboxamidoximes and carbothioamides |
JPS58208275A (ja) | 1982-05-20 | 1983-12-03 | Lion Corp | 5−アミノ−ピラゾ−ル誘導体及び該化合物を含有する抗腫瘍剤 |
DE3462259D1 (de) | 1983-07-22 | 1987-03-05 | Bayer Ag | Substituted furazans |
US4507485A (en) | 1984-01-23 | 1985-03-26 | Bristol-Myers Company | 3,4-Disubstituted-1,2,5-oxadiazoles having histamine H2 -receptor antagonist activity |
JPS60193968A (ja) | 1984-03-13 | 1985-10-02 | Toyo Jozo Co Ltd | シクロペンテン環を有するイミダゾ−ルアミドオキシムおよびその製造法 |
JPS6259283A (ja) | 1985-09-10 | 1987-03-14 | Kaken Pharmaceut Co Ltd | セフアロスポリン化合物 |
JP2696342B2 (ja) | 1988-06-27 | 1998-01-14 | 日本曹達株式会社 | アミジン誘導体、その製造方法及び殺ダニ剤・農園芸用殺菌剤 |
ES2051986T3 (es) | 1988-07-05 | 1994-07-01 | Akzo Nv | Compuestos con actividad broncodilatadora. |
JPH04297449A (ja) | 1991-03-27 | 1992-10-21 | Hokko Chem Ind Co Ltd | N−ヒドロキシベンジルグアニジン誘導体および農園芸用殺菌剤 |
JPH05186458A (ja) | 1991-04-26 | 1993-07-27 | Japan Tobacco Inc | 新規なベンゾピラン誘導体 |
FR2677019B1 (fr) | 1991-05-27 | 1994-11-25 | Pf Medicament | Nouvelles piperidines disubstituees-1,4, leur preparation et leur application en therapeutique. |
JP2709677B2 (ja) | 1992-06-19 | 1998-02-04 | 株式会社大塚製薬工場 | ホスホン酸ジエステル誘導体 |
FR2720396B1 (fr) | 1994-05-27 | 1996-06-28 | Adir | Nouveaux N-pyridyl carboxamides et dérivés leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
US5731315A (en) | 1995-06-07 | 1998-03-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds |
US5883102A (en) | 1995-10-17 | 1999-03-16 | Astra Pharmaceuticals Limited | Pharmaceutically active compounds |
WO1997030047A1 (en) | 1996-02-17 | 1997-08-21 | Agrevo Uk Limited | Fungicidal 1,2,4-oxadiazoles and analogues |
US5955495A (en) | 1996-05-03 | 1999-09-21 | Hoffmann-La Roche Inc. | Method of treating diseases of the CNS |
JPH11171702A (ja) | 1997-09-24 | 1999-06-29 | Takeda Chem Ind Ltd | 害虫防除方法 |
US6395876B1 (en) | 1997-12-05 | 2002-05-28 | Medical College Of Georgia Research Institute, Inc. | High-affinity tryptophan transporter |
NZ505002A (en) | 1997-12-10 | 2001-11-30 | Dainippon Ink & Chemicals | 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl or 1,2,3-thiadiazolyl oxime derivatives substituted by another heterocyclic group useful as agricultural chemicals |
CN1131863C (zh) | 1998-06-02 | 2003-12-24 | 住化武田农药株式会社 | 噁二唑啉衍生物及其作为杀虫剂的用途 |
FR2784678B1 (fr) | 1998-09-23 | 2002-11-29 | Sod Conseils Rech Applic | Nouveaux derives de n-(iminomethyl)amines, leur preparation, leur application a titre de medicaments et les compositions pharmaceutiques les contenant |
EP1075469B1 (en) | 1999-03-03 | 2004-05-26 | Samjin Pharmaceutical Co., Ltd. | Piperazine derivatives and process for the preparation thereof |
EP1165601A2 (de) | 1999-04-09 | 2002-01-02 | Basf Aktiengesellschaft | Prodrugs von thrombininhibitoren |
ES2244438T3 (es) | 1999-05-24 | 2005-12-16 | Mitsubishi Pharma Corporation | Compuestos de fenoxipropilamina. |
JP2001158785A (ja) | 1999-11-30 | 2001-06-12 | Takeda Chem Ind Ltd | 農薬組成物 |
JP2001158786A (ja) | 1999-11-30 | 2001-06-12 | Takeda Chem Ind Ltd | 哺乳動物の外部寄生虫防除剤 |
JP2003519676A (ja) | 2000-01-13 | 2003-06-24 | トゥラリック インコーポレイテッド | 抗菌剤 |
JP2001233861A (ja) | 2000-02-22 | 2001-08-28 | Ube Ind Ltd | ピラゾールオキシム化合物、その製法及び用途 |
ES2225624T3 (es) | 2000-06-28 | 2005-03-16 | Smithkline Beecham Plc | Procedimiento de molienda por via humeda. |
GB0108102D0 (en) | 2001-03-30 | 2001-05-23 | Pfizer Ltd | Compounds |
RS99503A (en) | 2001-06-18 | 2006-12-15 | Applied Research Systems Ars Holding N.V. | Pyrrolidine oxadiazole- and thiadiazole derivatives |
JP2005529850A (ja) | 2002-02-19 | 2005-10-06 | ファルマシア・イタリア・エス・ピー・エー | 三環系ピラゾール誘導体、その製造方法および抗腫瘍剤としてのその使用 |
GB0208224D0 (en) | 2002-04-10 | 2002-05-22 | Celltech R&D Ltd | Chemical compounds |
WO2003087347A1 (en) | 2002-04-12 | 2003-10-23 | Medical College Of Georgia Research Institute, Inc. | Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance |
EP1549632A4 (en) | 2002-05-28 | 2005-11-09 | Dimensional Pharm Inc | NEW THIOPHENAMIDINE, COMPOSITIONS AND METHOD FOR THE TREATMENT OF COMPLEMENTED DISEASES AND SUFFERING |
US7157462B2 (en) | 2002-09-24 | 2007-01-02 | Euro-Celtique S.A. | Therapeutic agents useful for treating pain |
CA2520172C (en) | 2003-03-27 | 2012-10-02 | Lankenau Institute For Medical Research | Novel methods for the treatment of cancer with an indoleamine 2, 3-dioxygenase inhibitor |
US7598287B2 (en) | 2003-04-01 | 2009-10-06 | Medical College Of Georgia Research Institute, Inc. | Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities |
AU2004267094A1 (en) | 2003-08-20 | 2005-03-03 | Vertex Pharmaceuticals Incorporated | (4 -amino -1,2, 5-oxadiazol-4-yl) -hetxiroaromatic compounds useful as protein kinase inhibitors |
DE10348022A1 (de) | 2003-10-15 | 2005-05-25 | Imtm Gmbh | Neue Dipeptidylpeptidase IV-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen |
DE10348023A1 (de) | 2003-10-15 | 2005-05-19 | Imtm Gmbh | Neue Alanyl-Aminopeptidasen-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen |
US7151097B2 (en) * | 2003-11-07 | 2006-12-19 | Pfizer Inc. | Bicyclic pyrazolyl and imidazolyl compounds and uses thereof |
CN101014580B (zh) | 2004-09-08 | 2011-05-04 | 田边三菱制药株式会社 | 吗啉化合物 |
WO2006067532A1 (en) | 2004-12-24 | 2006-06-29 | Prosidion Ltd | G-protein coupled receptor agonists |
US7429667B2 (en) | 2005-01-20 | 2008-09-30 | Ardea Biosciences, Inc. | Phenylamino isothiazole carboxamidines as MEK inhibitors |
PL1879573T3 (pl) | 2005-05-10 | 2013-05-31 | Incyte Holdings Corp | Modulatory 2,3-dioksygenazy indoloaminy i sposoby ich zastosowania |
WO2006133417A1 (en) | 2005-06-07 | 2006-12-14 | Valeant Pharmaceuticals International | Phenylamino isothiazole carboxamidines as mek inhibitors |
WO2007005807A2 (en) | 2005-06-30 | 2007-01-11 | Anthrogenesis Corporation | Repair of tympanic membrane using placenta derived collagen biofabric |
DE102005060466A1 (de) | 2005-12-17 | 2007-06-28 | Bayer Cropscience Ag | Carboxamide |
ES2540561T3 (es) | 2005-12-20 | 2015-07-10 | Incyte Corporation | N-hidroxiamidinoheterociclos como moduladores de indolamina 2,3-dioxigenasa |
US20070203140A1 (en) | 2006-02-09 | 2007-08-30 | Combs Andrew P | N-hydroxyguanidines as modulators of indoleamine 2,3-dioxygenase |
JP4297449B2 (ja) | 2006-05-12 | 2009-07-15 | 株式会社サクラクレパス | 墨汁 |
CL2007002650A1 (es) | 2006-09-19 | 2008-02-08 | Incyte Corp | Compuestos derivados de heterociclo n-hidroxiamino; composicion farmaceutica, util para tratar cancer, infecciones virales y desordenes neurodegenerativos entre otras. |
WO2008036643A2 (en) | 2006-09-19 | 2008-03-27 | Incyte Corporation | Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
US20080146624A1 (en) | 2006-09-19 | 2008-06-19 | Incyte Corporation | Amidines as modulators of indoleamine 2,3-dioxygenase |
EP2064207B1 (en) | 2006-09-19 | 2013-11-06 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
US20080182882A1 (en) | 2006-11-08 | 2008-07-31 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
AU2007333194A1 (en) | 2006-12-08 | 2008-06-19 | Exelixis, Inc. | LXR and FXR modulators |
CL2008000066A1 (es) | 2007-01-12 | 2008-08-01 | Smithkline Beecham Corp | Compuestos derivados de (5-hidroxi-3-oxo-2,3-dihidropiridazina-4-carbonil)glicina, inhibidores de hif prolil hidroxilasas; procedimiento de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso en el tratamiento de la anem |
CA2709784A1 (en) | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
WO2009128521A1 (ja) * | 2008-04-15 | 2009-10-22 | 帝人ファーマ株式会社 | システインプロテアーゼ阻害剤 |
AR098343A1 (es) | 2013-11-08 | 2016-05-26 | Incyte Holdings Corp | Proceso para la síntesis de un inhibidor de indolamina 2,3-dioxigenasa |
-
2014
- 2014-11-07 AR ARP140104196A patent/AR098343A1/es unknown
- 2014-11-07 MX MX2016005954A patent/MX366874B/es active IP Right Grant
- 2014-11-07 PE PE2021001747A patent/PE20220430A1/es unknown
- 2014-11-07 PL PL14812015T patent/PL3066085T3/pl unknown
- 2014-11-07 KR KR1020217032616A patent/KR102617531B1/ko active IP Right Grant
- 2014-11-07 TW TW103138838A patent/TWI651311B/zh active
- 2014-11-07 CR CR20160252A patent/CR20160252A/es unknown
- 2014-11-07 TW TW108102217A patent/TWI696618B/zh active
- 2014-11-07 SG SG11201603433UA patent/SG11201603433UA/en unknown
- 2014-11-07 EA EA201690959A patent/EA033667B1/ru unknown
- 2014-11-07 EP EP14812015.7A patent/EP3066085B1/en active Active
- 2014-11-07 HU HUE14812015A patent/HUE049337T2/hu unknown
- 2014-11-07 CA CA2929552A patent/CA2929552C/en active Active
- 2014-11-07 AU AU2014346647A patent/AU2014346647B2/en active Active
- 2014-11-07 BR BR112016009786-6A patent/BR112016009786B1/pt active IP Right Grant
- 2014-11-07 PE PE2016000604A patent/PE20160863A1/es unknown
- 2014-11-07 EP EP20169098.9A patent/EP3744715A1/en active Pending
- 2014-11-07 US US14/535,781 patent/US9321755B2/en active Active
- 2014-11-07 CN CN201910026055.2A patent/CN109810104B/zh active Active
- 2014-11-07 ME MEP-2020-146A patent/ME03792B/me unknown
- 2014-11-07 CR CR20190351A patent/CR20190351A/es unknown
- 2014-11-07 DK DK14812015.7T patent/DK3066085T3/da active
- 2014-11-07 BR BR122020009912-7A patent/BR122020009912B1/pt active IP Right Grant
- 2014-11-07 KR KR1020167015077A patent/KR102370067B1/ko active IP Right Grant
- 2014-11-07 PT PT148120157T patent/PT3066085T/pt unknown
- 2014-11-07 LT LTEP14812015.7T patent/LT3066085T/lt unknown
- 2014-11-07 ES ES14812015T patent/ES2799582T3/es active Active
- 2014-11-07 MY MYPI2016000827A patent/MY174254A/en unknown
- 2014-11-07 RS RS20200798A patent/RS60598B1/sr unknown
- 2014-11-07 SG SG10201803874PA patent/SG10201803874PA/en unknown
- 2014-11-07 TW TW109116698A patent/TWI775079B/zh active
- 2014-11-07 EA EA201991770A patent/EA201991770A1/ru unknown
- 2014-11-07 SI SI201431604T patent/SI3066085T1/sl unknown
- 2014-11-07 CN CN201480071825.0A patent/CN105899498B/zh active Active
- 2014-11-07 JP JP2016528055A patent/JP6461953B2/ja active Active
- 2014-11-07 WO PCT/US2014/064531 patent/WO2015070007A1/en active Application Filing
-
2016
- 2016-04-07 US US15/093,486 patent/US9873688B2/en active Active
- 2016-04-27 IL IL245314A patent/IL245314B/en active IP Right Grant
- 2016-05-02 PH PH12016500818A patent/PH12016500818A1/en unknown
- 2016-05-05 CL CL2016001082A patent/CL2016001082A1/es unknown
- 2016-05-06 MX MX2019008378A patent/MX2019008378A/es unknown
-
2017
- 2017-12-22 US US15/852,995 patent/US10280157B2/en active Active
-
2018
- 2018-10-02 JP JP2018187218A patent/JP6633163B2/ja active Active
-
2019
- 2019-01-21 AU AU2019200404A patent/AU2019200404B2/en active Active
- 2019-04-10 PH PH12019500770A patent/PH12019500770A1/en unknown
- 2019-07-01 IL IL267773A patent/IL267773B/en active IP Right Grant
- 2019-10-07 JP JP2019184589A patent/JP6883079B2/ja active Active
- 2019-10-07 JP JP2019184577A patent/JP6913725B2/ja active Active
-
2020
- 2020-07-13 HR HRP20201089TT patent/HRP20201089T1/hr unknown
- 2020-08-05 CY CY20201100726T patent/CY1123164T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040138448A1 (en) * | 2002-10-12 | 2004-07-15 | The Scripps Research Institute | Synthesis of non-symmetrical sulfamides using burgess-type reagents |
JP2011527686A (ja) * | 2008-07-08 | 2011-11-04 | インサイト・コーポレイション | インドールアミン2,3−ジオキシゲナーゼの阻害剤としての1,2,5−オキサジアゾール |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112341403A (zh) * | 2020-11-10 | 2021-02-09 | 南京工业大学 | 一种利用微流场反应技术制备3-氨基-4-偕胺肟基呋咱的方法 |
CN112341403B (zh) * | 2020-11-10 | 2022-06-28 | 南京工业大学 | 一种利用微流场反应技术制备3-氨基-4-偕胺肟基呋咱的方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6633163B2 (ja) | インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス | |
US9789094B2 (en) | 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase | |
TWI859554B (zh) | 用於合成吲哚胺2,3-雙加氧酶抑制劑之方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191007 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20191007 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200915 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200917 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20201211 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210210 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210309 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210330 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210428 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210507 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6883079 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |