JP2022545006A - インターフェロン遺伝子の刺激因子stingの二環式アゴニスト - Google Patents
インターフェロン遺伝子の刺激因子stingの二環式アゴニスト Download PDFInfo
- Publication number
- JP2022545006A JP2022545006A JP2022511099A JP2022511099A JP2022545006A JP 2022545006 A JP2022545006 A JP 2022545006A JP 2022511099 A JP2022511099 A JP 2022511099A JP 2022511099 A JP2022511099 A JP 2022511099A JP 2022545006 A JP2022545006 A JP 2022545006A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- substituted
- alkyl
- pharmaceutically acceptable
- acceptable salt
- 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
- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 10
- 108010050904 Interferons Proteins 0.000 title claims description 13
- 239000000556 agonist Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 238000000034 method Methods 0.000 claims abstract description 49
- 230000002829 reductive effect Effects 0.000 claims abstract description 31
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 230000014509 gene expression Effects 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 102000014150 Interferons Human genes 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 9
- 229940079322 interferon Drugs 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 8
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 7
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 7
- 230000004936 stimulating effect Effects 0.000 claims description 7
- 230000008685 targeting Effects 0.000 claims description 7
- 230000002601 intratumoral effect Effects 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 4
- 230000005865 ionizing radiation Effects 0.000 claims description 4
- 239000000611 antibody drug conjugate Substances 0.000 claims description 3
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 16
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 abstract description 6
- 125000004122 cyclic group Chemical group 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 4
- 102100035533 Stimulator of interferon genes protein Human genes 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract 1
- 230000009885 systemic effect Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- -1 nucleotide small molecule Chemical class 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 29
- 239000007787 solid Substances 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- BCXVFNXRWGQZTQ-UHFFFAOYSA-M NC=1C=2N(N=C(C=1)C(=O)NC1=C(C(=O)[O-])C=C(C(=C1)C#C)F)N=NN=2.[Li+] Chemical compound NC=1C=2N(N=C(C=1)C(=O)NC1=C(C(=O)[O-])C=C(C(=C1)C#C)F)N=NN=2.[Li+] BCXVFNXRWGQZTQ-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- XRILCFTWUCUKJR-INFSMZHSSA-N 2'-3'-cGAMP Chemical compound C([C@H]([C@H]1O)O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=NC=NC(N)=C5N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H]2N1C=NC2=C1NC(N)=NC2=O XRILCFTWUCUKJR-INFSMZHSSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- NSZZKAOZUOWJCS-UHFFFAOYSA-N NC=1C=2N(N=C(C=1)C=1OC(C3=C(N=1)C=C(C(=C3)F)C#C)=O)N=NN=2 Chemical compound NC=1C=2N(N=C(C=1)C=1OC(C3=C(N=1)C=C(C(=C3)F)C#C)=O)N=NN=2 NSZZKAOZUOWJCS-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000002849 thermal shift Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 4
- 108030002637 Cyclic GMP-AMP synthases Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 150000003857 carboxamides Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- BWVINRVLVUWORU-UHFFFAOYSA-N 3,6-dichloro-N-[(4-methoxyphenyl)methyl]pyridazin-4-amine Chemical compound C1=CC(OC)=CC=C1CNC1=CC(Cl)=NN=C1Cl BWVINRVLVUWORU-UHFFFAOYSA-N 0.000 description 3
- KHPDDHHEEXPNOA-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyrimidine-7-carboxylic acid Chemical compound N1=C(C(=O)O)C=CN2C(Br)=CN=C21 KHPDDHHEEXPNOA-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- LFVZTIFYPYIBFC-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)NC1=C(C(=O)OC)C=C(C(=C1)C#C)F)N=NN=2 Chemical compound C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)NC1=C(C(=O)OC)C=C(C(=C1)C#C)F)N=NN=2 LFVZTIFYPYIBFC-UHFFFAOYSA-N 0.000 description 3
- YEJLFIMCGROUKB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)OC)N=NN=2 Chemical compound C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)OC)N=NN=2 YEJLFIMCGROUKB-UHFFFAOYSA-N 0.000 description 3
- NPLAUOYMYXVTFC-UHFFFAOYSA-N ClC1=CC(=C(N=N1)C(=O)OC)NCC1=CC=C(C=C1)OC Chemical compound ClC1=CC(=C(N=N1)C(=O)OC)NCC1=CC=C(C=C1)OC NPLAUOYMYXVTFC-UHFFFAOYSA-N 0.000 description 3
- VLNAGIRKRPOEIR-UHFFFAOYSA-N ClC=1N=NC(=CC=1N(C(OC(C)(C)C)=O)CC1=CC=C(C=C1)OC)Cl Chemical compound ClC=1N=NC(=CC=1N(C(OC(C)(C)C)=O)CC1=CC=C(C=C1)OC)Cl VLNAGIRKRPOEIR-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- VSAGYUUYMGZVNW-UHFFFAOYSA-N O1C(CCCC1)N1N=CC(=C1)C1=CN=C2N1C=CC(=N2)C(=O)O Chemical compound O1C(CCCC1)N1N=CC(=C1)C1=CN=C2N1C=CC(=N2)C(=O)O VSAGYUUYMGZVNW-UHFFFAOYSA-N 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940044665 STING agonist Drugs 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- QAPSNMNOIOSXSQ-YNEHKIRRSA-N 1-[(2r,4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C1 QAPSNMNOIOSXSQ-YNEHKIRRSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 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
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZNKOLHVKRKSKHI-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N(C=1C=C(N=NC=1Cl)C(=O)OC)CC1=CC=C(C=C1)OC Chemical compound C(C)(C)(C)OC(=O)N(C=1C=C(N=NC=1Cl)C(=O)OC)CC1=CC=C(C=C1)OC ZNKOLHVKRKSKHI-UHFFFAOYSA-N 0.000 description 2
- PAZYCZBUCQIMAP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NC=1C=C(N=NC=1Cl)C(=O)OC Chemical compound C(C)(C)(C)OC(=O)NC=1C=C(N=NC=1Cl)C(=O)OC PAZYCZBUCQIMAP-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- UEALXPKDLOPVMM-UHFFFAOYSA-N ethyl imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound N1=C(C(=O)OCC)C=CN2C=CN=C21 UEALXPKDLOPVMM-UHFFFAOYSA-N 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 2
- 102000050022 human STING1 Human genes 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 239000012139 lysis buffer Substances 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
- 230000001404 mediated effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- YYSLAWXDXHVRHU-UHFFFAOYSA-N 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(C2OCCCC2)N=C1 YYSLAWXDXHVRHU-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- KUWRLKJYNASPQZ-UHFFFAOYSA-N 1h-imidazol-3-ium-2-amine;sulfate Chemical compound OS(O)(=O)=O.NC1=NC=CN1.NC1=NC=CN1 KUWRLKJYNASPQZ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LJDQXQOPXOLCHL-UHFFFAOYSA-N 3,4,6-trichloropyridazine Chemical compound ClC1=CC(Cl)=C(Cl)N=N1 LJDQXQOPXOLCHL-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- VERUFXOALATMPS-UHFFFAOYSA-N 5,5-diamino-2-(2-phenylethenyl)cyclohex-3-ene-1,1-disulfonic acid Chemical compound C1=CC(N)(N)CC(S(O)(=O)=O)(S(O)(=O)=O)C1C=CC1=CC=CC=C1 VERUFXOALATMPS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- UBSGIOKYLWENEG-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)O)N=NN=2 Chemical compound C(C)(C)(C)OC(=O)NC=1C=2N(N=C(C=1)C(=O)O)N=NN=2 UBSGIOKYLWENEG-UHFFFAOYSA-N 0.000 description 1
- KRJVDMGNOIWEQS-UHFFFAOYSA-N CC(C)(C)OC(=O)N(CC1=CC=C(C=C1)OC)C2=CC(=NN=C2Cl)C(=O)O Chemical compound CC(C)(C)OC(=O)N(CC1=CC=C(C=C1)OC)C2=CC(=NN=C2Cl)C(=O)O KRJVDMGNOIWEQS-UHFFFAOYSA-N 0.000 description 1
- DCGXCAKUESHINQ-UHFFFAOYSA-N CC(C)(C)OC(=O)NC1=CC(=NN=C1Cl)C(=O)O Chemical compound CC(C)(C)OC(=O)NC1=CC(=NN=C1Cl)C(=O)O DCGXCAKUESHINQ-UHFFFAOYSA-N 0.000 description 1
- GJGGLTAJGAFPBP-UHFFFAOYSA-N CCOC(=O)c1ccn2c(Br)cnc2n1 Chemical compound CCOC(=O)c1ccn2c(Br)cnc2n1 GJGGLTAJGAFPBP-UHFFFAOYSA-N 0.000 description 1
- GXSPSYXWTXQCJL-UHFFFAOYSA-N COC1=CC=C(CNC2=CC=3N(N=C2C(=O)O)N=NN=3)C=C1 Chemical compound COC1=CC=C(CNC2=CC=3N(N=C2C(=O)O)N=NN=3)C=C1 GXSPSYXWTXQCJL-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UZDBFZFMRCNYQU-UHFFFAOYSA-N ClC1=CC(=C(C(=O)OC)C=C1Cl)NC(=O)C1=NC=2N(C=C1)C(=CN=2)C#N Chemical compound ClC1=CC(=C(C(=O)OC)C=C1Cl)NC(=O)C1=NC=2N(C=C1)C(=CN=2)C#N UZDBFZFMRCNYQU-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 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-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
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 241000450599 DNA viruses Species 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
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- NDJKXXJCMXVBJW-UHFFFAOYSA-N Heptadecane Natural products CCCCCCCCCCCCCCCCC NDJKXXJCMXVBJW-UHFFFAOYSA-N 0.000 description 1
- 101001011382 Homo sapiens Interferon regulatory factor 3 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QMNQGYKEAVREKX-UHFFFAOYSA-N IC1=CN=C2N1C=CC(=N2)C(=O)OC Chemical compound IC1=CN=C2N1C=CC(=N2)C(=O)OC QMNQGYKEAVREKX-UHFFFAOYSA-N 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102100029843 Interferon regulatory factor 3 Human genes 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100043703 Mus musculus Sting1 gene Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- LIIBUVVIVPQKGR-UHFFFAOYSA-N NC1=C(C(=O)OC)C=C(C(=C1)C#C)F Chemical compound NC1=C(C(=O)OC)C=C(C(=C1)C#C)F LIIBUVVIVPQKGR-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- YSYZZUGVNCFTPN-UHFFFAOYSA-N O1C(CCCC1)N1N=CC(=C1)C1=CN=C2N1C=CC(=N2)C(=O)OC Chemical compound O1C(CCCC1)N1N=CC(=C1)C1=CN=C2N1C=CC(=N2)C(=O)OC YSYZZUGVNCFTPN-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 229910052771 Terbium Inorganic materials 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- OISFUZRUIGGTSD-LJTMIZJLSA-N azane;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound N.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO OISFUZRUIGGTSD-LJTMIZJLSA-N 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 239000011230 binding agent Substances 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PKFDLKSEZWEFGL-MHARETSRSA-N c-di-GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=C(C(NC(N)=N5)=O)N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 PKFDLKSEZWEFGL-MHARETSRSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003427 indacenyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- FZRNJOXQNWVMIH-UHFFFAOYSA-N lithium;hydrate Chemical compound [Li].O FZRNJOXQNWVMIH-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- WPXDGHPUISYMNL-SNAWJCMRSA-N methyl (E)-4-ethoxy-2-oxobut-3-enoate Chemical compound CCO\C=C\C(=O)C(=O)OC WPXDGHPUISYMNL-SNAWJCMRSA-N 0.000 description 1
- KJKMOADDOGZYQC-UHFFFAOYSA-N methyl 2-(2-trimethylsilylethynyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1C#C[Si](C)(C)C KJKMOADDOGZYQC-UHFFFAOYSA-N 0.000 description 1
- GPQSHTPSMYICPA-UHFFFAOYSA-N methyl 2-amino-4,5-dichlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=C(Cl)C=C1N GPQSHTPSMYICPA-UHFFFAOYSA-N 0.000 description 1
- QTZQOFPIDBEWIC-UHFFFAOYSA-N methyl 2-amino-5-fluoro-4-(2-trimethylsilylethynyl)benzoate Chemical compound NC1=C(C(=O)OC)C=C(C(=C1)C#C[Si](C)(C)C)F QTZQOFPIDBEWIC-UHFFFAOYSA-N 0.000 description 1
- OMKQKBOYVRHLRP-UHFFFAOYSA-N methyl 4-(2-trimethylsilylethynyl)benzoate Chemical compound COC(=O)C1=CC=C(C#C[Si](C)(C)C)C=C1 OMKQKBOYVRHLRP-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- SWXLYVRMAFZYTP-UHFFFAOYSA-N methyl imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound N1=C(C(=O)OC)C=CN2C=CN=C21 SWXLYVRMAFZYTP-UHFFFAOYSA-N 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 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@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[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 CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000013379 physicochemical characterization Methods 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 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
- 230000002335 preservative effect Effects 0.000 description 1
- 238000002810 primary assay Methods 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
cGAS-STINGシグナル伝達経路は、哺乳動物宿主細胞が多様なDNAおよびRNAウイルスを除去するために開始する自然免疫応答において重要な役割を果たす。STING(Stimulator of Interferon Genes)は、ミトコンドリア関連膜に部分的に局在する小胞体(ER)常在シグナル伝達タンパク質であり、免疫および非免疫細胞型の両方で広く発現される。環状GMP-AMPシンターゼ(cGAS)によりサイトゾルDNAに反応して産生される2'-3'cGAMPを含む、環状ジヌクレオチド(CDN)に反応して、STINGは核周囲領域に移動し、ここでTBK1-/IRF3-依存的様式でI型インターフェロン(IFN)および炎症性サイトカイン産生を急速に誘導する。STINGはサイトゾルDNAと直接結合することも判明しているが、直接的DNAセンシング活性の生理学的関連性はなお十分に特徴づけるべきである。
様々な態様において、本開示はインターフェロン遺伝子の刺激因子(STING)のアゴニストを提供し、これは腫瘍の処置に使用することができる。
式中
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)-であり;
各R1は独立に、H、F、Cl、C1~C6-アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、ハロアルキル、またはC3~C6-シクロアルキルであり;
または両方のR1は、それらが結合している炭素原子と一緒に、縮合フェニルを形成し;
Rは、H、-((C1~C6-アルキル)OC(O)OC1~C6-アルキル)で置換されていてもよいアルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH2、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、C1~C6-アルキル、-S(O)2(C1~C6-アルキル)、-S(O)(C1~C6-アルキル)、アルキルニトリル、アルコキシル、およびハロアルキルからなる組よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る。
式中
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)-であり;
各R1は独立に、H、F、Cl、C1~C6-アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、ハロアルキル、またはC3~C6-シクロアルキルであり;
または両方のR1は、それらが結合している炭素原子と一緒に、縮合フェニルを形成し;
Rは、H、-((C1~C6-アルキル)OC(O)C1~C6-アルキル)で置換されていてもよいアルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH2、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、C1~C6-アルキル、-S(O)2(C1~C6-アルキル)、-S(O)(C1~C6-アルキル)、アルキルニトリル、アルコキシル、およびハロアルキルからなる群よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る。より具体的には、例示的態様ごとに、本開示の化合物は、以下の表1に示す任意の具体的化合物を含む。
多様な免疫腫瘍学的適用のためのSTING経路アゴニストの開発に多大な関心がある。最も顕著なことに、STING経路アゴニストは、チェックポイント遮断単独に反応しない患者において、免疫チェックポイント標的薬物を含む併用療法の一部として重要な適用の可能性を有する。
などの生物学的に等価な置換物で置き換えられてもよく、ここでRは本明細書に定義するRAと同じ定義を有する。例えば、The Practice of Medicinal Chemistry (Academic Press: New York, 1996), at page 203を参照されたい。
式中、波線は結合の位置を示す。
本開示は、1つの態様において、ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法も提供する。この方法は、有効用量の本明細書に記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む。
本開示は、別の態様において、本明細書に記載の化合物またはその薬学的に許容される塩を薬学的に許容される担体または賦形剤との組み合わせで含む薬学的組成物を提供する。
略語。 以下の略語を用いる:テトラヒドロフラン(THF)、ジクロロメタン(DCM)、N,N-ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、ジメチルスルホキシド(DMSO)、トリフルオロ酢酸(TFA)、トリエチルアミン(TEA)、ジイソプロピルエチルアミン(DIPEA)、(1-シアノ-2-エトキシ-2-オキソエチリデンアミノオキシ)ジメチルアミノ-モルホリノ-カルベニウムヘキサフルオロホスフェート(COMU)、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート、N-[(ジメチルアミノ)-1H-1,2,3-トリアゾロ-[4,5-b]ピリジン-1-イルメチレン]-N-メチルメタンアミニウムヘキサフルオロホスフェートN-オキシド(HATU)。
THF(450mL)中の3,4,6-トリクロロピリダジン(45.0g、245mmol)の溶液に、(4-メトキシフェニル)メタンアミン(101g、736mmol)を加え、次いで混合物を50℃で0.5時間撹拌した。混合物を水(1000mL)で希釈し、EtOAc(1000mL×3)で抽出した。合わせた有機層を食塩水(300mL×2)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィで精製して、3,6-ジクロロ-N-(4-メトキシベンジル)ピリダジン-4-アミン(70.0g、純度97%、収率97%)を白色固体で得た。LCMS (ESI): m/z 283.9 [M+H]+。
THF(700mL)中の3,6-ジクロロ-N-(4-メトキシベンジル)ピリダジン-4-アミン(70.0g、246mmol)の溶液に、Et3N(49.9g、492mmol)、DMAP(15.0g、123mmol)およびBoc2O(79.2mL、345mmol)を加えた。25℃で0.5時間撹拌した後、混合物を水(1000mL)で希釈し、次いでEtOAc(1000mL×3)で抽出した。合わせた層を食塩水(500mL×2)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィで精製して、(3,6-ジクロロピリダジン-4-イル)(4-メトキシベンジル)カルバミン酸tert-ブチル(77g、収率67%)を白色固体で得た。LCMS (ESI): m/z 384.1 [M+H]+。
メタノール(500mL)中の(3,6-ジクロロピリダジン-4-イル)(4-メトキシベンジル)カルバミン酸tert-ブチル(36.5g、95.0mmol)の溶液に、Et3N(39.7mL、285mmol)およびPd(PPh3)2Cl(6.95g、9.50mmol)を加えた。混合物を一酸化炭素(50psi)雰囲気下、40℃で4時間撹拌した。混合物を水(500mL)で希釈し、EtOAc(500mL×3)で抽出した。合わせた有機層を食塩水(300mL×2)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィで精製して、5-((tert-ブトキシカルボニル)(4-メトキシベンジル)アミノ)-6-クロロピリダジン-3-カルボン酸メチル(22.9g、収率47%)を白色固体で得た。LCMS (ESI): m/z 408.1 [M+H]+
アセトニトリル(75.0mL)および水(75.0mL)中の5-((tert-ブトキシカルボニル)(4-メトキシベンジル)アミノ)-6-クロロピリダジン-3-カルボキシレート(15.0g、36.7mmol)の溶液に、CAN(40.3g、73.6mmol)を0℃で加え、次いで混合物を0.5時間撹拌した。混合物を水(200mL)で希釈し、EtOAc(100mL×3)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィで精製して、5-((tert-ブトキシカルボニル)アミノ)-6-クロロピリダジン-3-カルボン酸メチル(7.20g、収率65%)を白色固体で得た。LCMS (ESI): m/z 288.0 [M+H]+。
DMSO(43.0mL)中の5-((tert-ブトキシカルボニル)アミノ)-6-クロロピリダジン-3-カルボキシレート(4.30g、13.6mmol)溶液に、アジ化ナトリウム(2.65g、40.8mmol)を加えた。50℃で2時間撹拌した後、混合物を水(200mL)で希釈し、EtOAc(200mL×3)で抽出した。合わせた有機層を水(200mL×3)および食塩水(200mL×2)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィで精製して、8-((tert-ブトキシカルボニル)アミノ)テトラゾロ[1,5-b]ピリダジン-6-カルボン酸メチル(2.80g、収率66%)を白色固体で得た。
THF(5mL)中の8-((tert-ブトキシカルボニル)アミノ)テトラゾロ[1,5-b]ピリダジン-6-カルボン酸メチル(250mg、0.85mmol)の溶液に、水(5mL)中の水酸化リチウム一水和物(143mg、3.4mmol)の溶液を0℃で加えた。混合物を25℃で4時間撹拌した。反応の完了後、3M HClを加えて反応混合物を中和し、沈澱をろ過し、冷水(1mL×2)で洗浄して、A(191mg、収率80%)を白色固体で得た。
DMSO(2mL)中の化合物4,6-ジクロロピリダジン-3-カルボン酸メチル(207mg、1mmol)およびEt3N(279μL、2mmol)の溶液に、4-メトキシベンジルアミン (144μL、1.1mmol)を加え、反応混合物を室温で終夜撹拌した。反応の完了後、水(10mL)を加え、白色沈澱が形成された。混合物をろ過し、水で洗浄して、6-クロロ-4-((4-メトキシベンジル)アミノ)ピリダジン-3-カルボン酸メチル(257mg、収率84%)を白色固体で得た。LCMS (ESI): m/z 308.0 [M+H]+。
DMSO(3mL)中の6-クロロ-4-((4-メトキシベンジル)アミノ)ピリダジン-3-カルボン酸メチル(257mg、0.84mmol)の溶液に、アジ化ナトリウム(109mg、1.68mmol)を加え、100℃で16時間撹拌した。反応の完了後、水(5mL)を加え、黄色沈澱が形成された。混合物を0℃で10分間維持し、ろ過し、水(2mL×2)で洗浄して、黄色固体を得た。固体を水(10mL)に懸濁し、HCl(3M)を加えて中和した。懸濁液をろ過してB(183mg、収率73%)を黄色固体で得た。
EtOH(100mL)中の1H-イミダゾル-2-アミンヘミ硫酸塩(8.5g、64.33mmol)の溶液に、ナトリウムメトキシド(4.4g、82.2mmol)を加え、得られた混合物を90℃で30分間撹拌した。次いで、これを室温まで冷却し、EtOH(40mL)中の(E)-4-エトキシ-2-オキソブタ-3-エン酸メチル(10g、63.29mmol)の溶液を加えた。反応混合物を還流するまでゆっくり加熱し、16時間撹拌した。反応の完了後、室温まで冷却し、揮発性物質を減圧下で除去した。残渣をカラムクロマトグラフィ(0~4%MeOH/DCM)で精製して、イミダゾ[1,2-a]ピリミジン-7-カルボン酸メチル(5.2g、収率43%)をオフホワイト固体で得た。
MeOH(52mL)中のイミダゾ[1,2-a]ピリミジン-7-カルボン酸エチル(5.2g、27.2mmol)の懸濁液に、KBr(3.24g、27.2mmol)および酢酸ナトリウム(3.43g、40.8mmol)を0℃、窒素雰囲気下で加えた。これに臭素(4.78g、29.9mmol)を10~15分かけて加えた。完了後、反応を1M Na2SO3水溶液(10mL)で停止した。次いで、揮発性物質を減圧下で除去し、飽和NaHCO3溶液(30mL)を残渣に加えた。得られた固体をろ取し、カラムクロマトグラフィ(0~2%MeOH/DCM)で精製して、C(5.3g、収率72%)をオフホワイト固体で得た。
本開示のすべての化合物を、以下に例示する手順を用いて調製した。
A(27.8mg、0.1mmol)の溶液に、HATU(48mg、0.15mmol)、2-アミノ-4-エチニル-5-フルオロ安息香酸メチル(19.4mg、0.11mmol)およびDIPEA(35μL、0.2mmol)を加え、反応混合物を50℃で終夜撹拌した。粗製混合物を分取HPLCで精製して、2-(8-((tert-ブトキシカルボニル)アミノ)テトラゾロ[1,5-b]ピリダジン-6-カルボキサミド)-4-エチニル-5-フルオロ安息香酸メチルを白色固体で得た(28mg、収率51%)。
CH2Cl2(0.8mL)中の2-(8-((tert-ブトキシカルボニル)アミノ)テトラゾロ[1,5-b]ピリダジン-6-カルボキサミド)-4-エチニル-5-フルオロ安息香酸メチル(28mg、0.061mmol)の溶液に、TFA(0.4mL)を加え、反応混合物を室温で1時間撹拌した。反応の完了後、混合物を減圧下で濃縮した。次いで、粗製混合物をTHF(2mL)に溶解し、水酸化リチウム水溶液(310μL、0.31mmol、1M)を加え、50℃で6時間撹拌した。反応の完了後、THFを減圧下で除去し、残渣を水(1mL)に懸濁した。これをろ過し、冷水(0.5mL×2)およびアセトニトリル(0.5mL)で洗浄して、化合物1(リチウム塩、14.5mg、収率68%)を白色固体で得た。
5、6、7、8、9、10、11、14、15、16、17、18、19、21、22、24、25、26、28、29、30、31、32、33、34、35、36、38、39、40、41、42、43、45、47、50、55、56、58、64、65、66、67、68、69、70、71、72、73、74、79、80、77、78、81、82、83、84、85および86など。
塩化チオニル0.6mL中の化合物1(20mg、0.06mmol)の懸濁液および混合物を2時間加熱還流した。次いで、過剰のチオニルを減圧下で除去した。固体を無水アセトニトリル1mLに溶解し、無水アセトニトリル1mL中のDIPEA(20μL、0.12mmol)の溶液を室温で加えた。30分間撹拌した後、得られた沈澱を分離し、アセトニトリルで洗浄して、生成物(15mg、収率77%)を得た。
水酸化リチウムの水溶液(0.327g、7.8mmol、2mL水)をTHF(8mL)中のC(1.4g、5.2mmol)の溶液に室温で加えた。反応混合物を同じ温度で1時間撹拌した。反応の完了後、溶媒を減圧下で除去し、水層を0℃で2N HClを用いて酸性化した。得られた固体をろ取し、冷水(3mL×2)で洗浄し、乾燥して、3-ブロモイミダゾ[1,2-a]ピリミジン-7-カルボン酸(1.0g、収率79%)をオフホワイト固体で得た。
DMF(14mL)中の3-ブロモイミダゾ[1,2-a]ピリミジン-7-カルボン酸(1.4g、5.8mmol)の溶液に、DIPEA(3.8g、29.2mmol)およびHATU(3.3g、8.7mmol)を0℃、窒素雰囲気下で加えた。これを10分間撹拌した後、2-アミノ-4,5-ジクロロ安息香酸メチル(1.9g、8.7mmol)を加えた。反応混合物を80℃で5時間撹拌した。反応の完了後、室温まで冷却し、飽和NaHCO3溶液(30mL)を加えた。得られた固体をろ取し、カラムクロマトグラフィで精製して、2-(3-ブロモイミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-4,5-ジクロロ安息香酸メチル(1.0g、収率39%)をオフホワイト固体で得た。
DMF(4mL)中の2-(3-ブロモイミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-4,5-ジクロロ安息香酸メチル(0.220g、0.5mmol)の溶液に、CuCN(0.157g、1.75mmol)を加え、これをマイクロ波反応器内、140℃で2時間(1時間+1時間の間隔)照射した。反応混合物をEtOAc(25mL)で希釈し、飽和NaHCO3(10mL)溶液、水(10mL×2)、食塩水(10mL)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(0~30%EtOAc/PE)で精製して0.11gの粗生成物を得、これを分取HPLCでさらに精製して、化合物3(11mg、収率6%)をオフホワイト固体で得た。
THF(3mL)中の1-(テトラヒドロ-2H-ピラン-2-イル)-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(413mg、1.48 mmol、1.5当量)、3-ヨードイミダゾ[1,2-a]ピリミジン-7-カルボン酸メチル(0.3g、989umol、1当量)、K3PO4(315mg、1.48mmol、1.5当量)およびSPhos Pd G3(154mg、197umol、0.2当量)の混合物を脱気し、N2で3回パージした。混合物を60℃で2時間、N2雰囲気下で撹拌した。粗製反応混合物を逆相Combi-flash(0.1%FA条件)で精製して、化合物3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボン酸メチル(120mg、366umol、収率37%)を黄色固体で得た。LCMS (ESI): m/z 328.1 [M+H]+。
THF(0.5mL)およびH2O(0.5mL)中の3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボン酸メチル(100mg、305umol、1当量)の混合物に、LiOH・H2O(12.8mg、305umol、1当量)を20℃で加えた。混合物を20℃で0.5時間撹拌し、次いで濃縮して、化合物3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボン酸(85mg、粗製)を黄色固体で得た。LCMS (ESI): m/z 314.1 [M+H]+。
Py(0.5mL)中の3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボン酸(50mg、159umol、1当量)および2-アミノ-5-フルオロ-4-((トリメチルシリル)エチニル)安息香酸メチル(42.3mg、159umol、1当量)の混合物に、POCl3(73.4mg、478umol、44.4uL、3当量)を15℃で加えた。混合物を15℃で30分間撹拌し、次いでH2O(20mL)で希釈し、EA(10mL×3)で抽出した。合わせた有機層をNa2SO4で乾燥し、ろ過し、減圧下で濃縮して、残渣を得た。残渣を分取HPLCで精製して、5-フルオロ-2-(3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-4-((トリメチルシリル)エチニル)安息香酸メチル(75mg、133umol、2段階の収率74%)を黄色固体で得た。
DCM(1mL)中の5-フルオロ-2-(3-(1-(テトラヒドロ-2H-ピラン-2-イル)-1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-4-((トリメチルシリル)エチニル)安息香酸メチル(15mg、26.7umol、1当量)の混合物に、TFA(462mg、4.05mmol、0.3mL、151当量)を15℃で一度に加えた。混合物を15℃で15分間撹拌し、次いで濃縮して、残渣を得た。残渣を分取HPLC(カラム:Shim-pack C18 150*25*10um;移動相:[水(0.225%FA)-ACN];B%:62%~82%、10分)で精製して、化合物2-(3-(1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-5-フルオロ-4-((トリメチルシリル)エチニル)安息香酸メチル(8mg、16.7umol、収率62%)を黄色固体で得た。LCMS (ESI): m/z 477.0 [M+H]+。
THF(0.1mL)およびH2O(0.1mL)中の2-(3-(1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-5-フルオロ-4-((トリメチルシリル)エチニル)安息香酸メチル(15mg、31.4umol、1当量)の混合物に、LiOH・H2O(1.45mg、34.62umol、1.1当量)を15℃で一度に加えた。混合物を15℃で30分間撹拌した。混合物を1N HClでpH=6として反応停止し、次いで減圧下で濃縮して除去した。沈澱をろ過し、ろ過ケークを減圧下で乾燥して、化合物2-(3-(1H-ピラゾル-4-イル)イミダゾ[1,2-a]ピリミジン-7-カルボキサミド)-4-エチニル-5-フルオロ安息香酸(4.28mg、10.9umol、収率34%、純度100%)を黄色固体で得た。
[本発明1001]
式(I)もしくは式(II)の化合物、またはその薬学的に許容される塩:
式中
Xは、S、-N=C(R 1 )-、または-C(R 1 )=C(R 1 )-であり;
各R 1 は独立に、H、F、Cl、C 1 ~C 6 -アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、ハロアルキル、またはC 3 ~C 6 -シクロアルキルであり;
または両方のR 1 は、それらが結合している炭素原子と一緒に、縮合フェニルを形成し;
RはH、-((C 1 ~C 6 -アルキル)OC(O)OC 1 ~C 6 -アルキル)で置換されていてもよいアルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH 2 、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、C 1 ~C 6 -アルキル、-S(O) 2 (C 1 ~C 6 -アルキル)、-S(O)(C 1 ~C 6 -アルキル)、アルキルニトリル、アルコキシル、およびハロアルキルからなる組よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る。
[本発明1002]
式(I)のものであり、
式中、
Xは、S、-N=C(R 1 )-、または-C(R 1 )=C(R 1 )-であり;
各R 1 は独立に、H、F、Cl、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;
Rは、H、アルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH 2 、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、アルキルニトリル、アルコキシル、およびハロアルキルからなる組よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る、
本発明1001の化合物。
[本発明1003]
式(II)のものである、本発明1001の化合物。
[本発明1004]
環Aが、無置換であるかまたは置換されており、かつ下記:
からなる群より選択されるものであり、式中、波線は結合の位置を示す、
本発明1001~1003のいずれかの化合物。
[本発明1005]
以下の表:
から選択されるものである、本発明1001の化合物。
[本発明1006]
ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法であって、有効用量の本発明1001~1005のいずれかの化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
[本発明1007]
患者における腫瘍の処置方法であって、有効用量の本発明1001~1005のいずれかの化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
[本発明1008]
投与する段階が、経口もしくは腫瘍内投与、または両方を含む、本発明1006または1007の方法。
[本発明1009]
投与する段階が、前記化合物を、抗体-薬物結合体として、またはリポソーム製剤で患者に投与することを含む、本発明1006または1007の方法。
[本発明1010]
有効用量の免疫チェックポイント標的薬物を投与する段階
をさらに含む、本発明1006または1007の方法。
[本発明1011]
免疫チェックポイント標的薬物が、抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体、または抗4-1BB抗体を含む、本発明1010の方法。
[本発明1012]
電離放射線または抗がん剤の投与
をさらに含む、本発明1006または1007の方法。
[本発明1013]
本発明1001~1005のいずれかの化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを含む、薬学的組成物。
[本発明1014]
ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法において用いるための、本発明1001~1005のいずれかの化合物またはその薬学的に許容される塩。
[本発明1015]
患者における腫瘍の処置方法において用いるための、本発明1001~1005のいずれかの化合物またはその薬学的に許容される塩。
[本発明1016]
経口もしくは腫瘍内投与、または両方により患者に投与される、本発明1014または1015の使用のための化合物。
Claims (16)
- 式(I)もしくは式(II)の化合物、またはその薬学的に許容される塩:
式中
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)-であり;
各R1は独立に、H、F、Cl、C1~C6-アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、ハロアルキル、またはC3~C6-シクロアルキルであり;
または両方のR1は、それらが結合している炭素原子と一緒に、縮合フェニルを形成し;
RはH、-((C1~C6-アルキル)OC(O)OC1~C6-アルキル)で置換されていてもよいアルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH2、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、C1~C6-アルキル、-S(O)2(C1~C6-アルキル)、-S(O)(C1~C6-アルキル)、アルキルニトリル、アルコキシル、およびハロアルキルからなる組よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る。 - 式(I)のものであり、
式中、
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)-であり;
各R1は独立に、H、F、Cl、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;
Rは、H、アルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;かつ
環Aは、NH2、シアノ、NHC(=O)O-tBu、OH、カルボキサミド、アルキルニトリル、アルコキシル、およびハロアルキルからなる組よりそれぞれ独立に選択される0、1、2、3、または4つの置換基で置換された、3、4、または5つのN原子を含む二環式完全芳香族または部分還元ヘテロアリール環系であり、ただし、部分還元ヘテロアリール環系はオキソ基でも置換され得る、
請求項1記載の化合物。 - 式(II)のものである、請求項1記載の化合物。
- ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法であって、有効用量の請求項1~5のいずれか一項記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
- 患者における腫瘍の処置方法であって、有効用量の請求項1~5のいずれか一項記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
- 投与する段階が、経口もしくは腫瘍内投与、または両方を含む、請求項6または7記載の方法。
- 投与する段階が、前記化合物を、抗体-薬物結合体として、またはリポソーム製剤で患者に投与することを含む、請求項6または7記載の方法。
- 有効用量の免疫チェックポイント標的薬物を投与する段階
をさらに含む、請求項6または7記載の方法。 - 免疫チェックポイント標的薬物が、抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体、または抗4-1BB抗体を含む、請求項10記載の方法。
- 電離放射線または抗がん剤の投与
をさらに含む、請求項6または7記載の方法。 - 請求項1~5のいずれか一項記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを含む、薬学的組成物。
- ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法において用いるための、請求項1~5のいずれか一項記載の化合物またはその薬学的に許容される塩。
- 患者における腫瘍の処置方法において用いるための、請求項1~5のいずれか一項記載の化合物またはその薬学的に許容される塩。
- 経口もしくは腫瘍内投与、または両方により患者に投与される、請求項14または15記載の使用のための化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962889679P | 2019-08-21 | 2019-08-21 | |
US62/889,679 | 2019-08-21 | ||
PCT/US2020/070444 WO2021035258A1 (en) | 2019-08-21 | 2020-08-21 | Bicyclic agonists of stimulator of interferon genes sting |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022545006A true JP2022545006A (ja) | 2022-10-24 |
JP7414965B2 JP7414965B2 (ja) | 2024-01-16 |
Family
ID=72381173
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022511099A Active JP7414965B2 (ja) | 2019-08-21 | 2020-08-21 | インターフェロン遺伝子の刺激因子stingの二環式アゴニスト |
Country Status (10)
Country | Link |
---|---|
US (1) | US20220332720A1 (ja) |
EP (1) | EP4017593A1 (ja) |
JP (1) | JP7414965B2 (ja) |
KR (1) | KR20220066067A (ja) |
CN (1) | CN115003383A (ja) |
AU (1) | AU2020333990B2 (ja) |
CA (1) | CA3151850A1 (ja) |
IL (1) | IL290771A (ja) |
MX (1) | MX2022002152A (ja) |
WO (1) | WO2021035258A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2021206158A1 (ja) | 2020-04-10 | 2021-10-14 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996016954A1 (en) * | 1994-12-02 | 1996-06-06 | Agrevo Uk Limited | Derivatives of anthranilic acid useful as fungicides |
JP2008273950A (ja) * | 2007-03-30 | 2008-11-13 | Fujifilm Corp | 紫外線吸収剤およびヘテロ環化合物 |
WO2018067423A1 (en) * | 2016-10-04 | 2018-04-12 | Merck Sharp & Dohme Corp. | BENZO[b]THIOPHENE COMPOUNDS AS STING AGONISTS |
WO2018200812A1 (en) * | 2017-04-28 | 2018-11-01 | Novartis Ag | Antibody conjugates comprising sting agonist |
WO2019055750A1 (en) * | 2017-09-15 | 2019-03-21 | Aduro Biotech, Inc. | PYRAZOLOPYRIMIDINONE COMPOUNDS AND USES THEREOF |
WO2019165032A1 (en) * | 2018-02-21 | 2019-08-29 | The Scripps Research Institute | Agonists of stimulator of interferon genes sting |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4657893A (en) * | 1984-05-09 | 1987-04-14 | Syntex (U.S.A.) Inc. | 4H-3,1-benzoxazin-4-ones and related compounds and use as enzyme inhibitors |
US5262537A (en) * | 1993-03-19 | 1993-11-16 | Anaquest, Inc. | Derivatives of 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridinyl-6-carboxylic acid |
WO2003002558A1 (fr) * | 2001-06-13 | 2003-01-09 | Asahi Kasei Pharma Corporation | Remede pour maladies infectieuses virales |
AU2003211428A1 (en) * | 2002-02-22 | 2003-09-09 | Teijin Limited | Pyrrolopyrimidine derivative |
RU2341527C1 (ru) * | 2007-07-17 | 2008-12-20 | Общество С Ограниченной Ответственностью "Исследовательский Институт Химического Разнообразия" | Аннелированные азагетероциклы, включающие пиримидиновый фрагмент, способ их получения и ингибиторы pi3k киназ |
DK3366688T3 (da) * | 2010-12-08 | 2022-05-02 | Us Health | Substituerede pyrazolpyrimidiner som glucocerebrosidaseaktivatorer |
EP2928470A4 (en) * | 2012-12-07 | 2015-12-16 | Siga Technologies Inc | THIENOPYRIDINE DERIVATIVES FOR THE TREATMENT AND PREVENTION OF DENGUE VIRUS INFECTIONS |
US20170146519A1 (en) * | 2015-11-20 | 2017-05-25 | Oregon Health & Science University | Sting agonists and methods of selecting sting agonists |
GB2563642A (en) * | 2017-06-22 | 2018-12-26 | Curadev Pharma Ltd | Small molecule modulators of human STING |
-
2020
- 2020-08-21 AU AU2020333990A patent/AU2020333990B2/en active Active
- 2020-08-21 US US17/753,139 patent/US20220332720A1/en active Pending
- 2020-08-21 CA CA3151850A patent/CA3151850A1/en active Pending
- 2020-08-21 CN CN202080071332.2A patent/CN115003383A/zh active Pending
- 2020-08-21 MX MX2022002152A patent/MX2022002152A/es unknown
- 2020-08-21 KR KR1020227009232A patent/KR20220066067A/ko active Search and Examination
- 2020-08-21 WO PCT/US2020/070444 patent/WO2021035258A1/en unknown
- 2020-08-21 JP JP2022511099A patent/JP7414965B2/ja active Active
- 2020-08-21 EP EP20767941.6A patent/EP4017593A1/en active Pending
-
2022
- 2022-02-21 IL IL290771A patent/IL290771A/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996016954A1 (en) * | 1994-12-02 | 1996-06-06 | Agrevo Uk Limited | Derivatives of anthranilic acid useful as fungicides |
JP2008273950A (ja) * | 2007-03-30 | 2008-11-13 | Fujifilm Corp | 紫外線吸収剤およびヘテロ環化合物 |
WO2018067423A1 (en) * | 2016-10-04 | 2018-04-12 | Merck Sharp & Dohme Corp. | BENZO[b]THIOPHENE COMPOUNDS AS STING AGONISTS |
WO2018200812A1 (en) * | 2017-04-28 | 2018-11-01 | Novartis Ag | Antibody conjugates comprising sting agonist |
WO2019055750A1 (en) * | 2017-09-15 | 2019-03-21 | Aduro Biotech, Inc. | PYRAZOLOPYRIMIDINONE COMPOUNDS AND USES THEREOF |
WO2019165032A1 (en) * | 2018-02-21 | 2019-08-29 | The Scripps Research Institute | Agonists of stimulator of interferon genes sting |
Non-Patent Citations (3)
Title |
---|
"RN 675142-39-9 REGISTRY", DATABASE REGISTRY [ONLINE] RETRIEVED FROM STN, JPN7023001241, ISSN: 0005024127 * |
"RN 786728-68-5 REGISTRY", DATABASE REGISTRY [ONLINE] RETRIEVED FROM STN, JPN7023001242, ISSN: 0005024126 * |
"RN 919938-80-0 REGISTRY", DATABASE REGISTRY [ONLINE] RETRIEVED FROM STN, JPN7023001243, ISSN: 0005024125 * |
Also Published As
Publication number | Publication date |
---|---|
JP7414965B2 (ja) | 2024-01-16 |
KR20220066067A (ko) | 2022-05-23 |
CN115003383A (zh) | 2022-09-02 |
CA3151850A1 (en) | 2021-02-25 |
WO2021035258A1 (en) | 2021-02-25 |
AU2020333990A1 (en) | 2022-04-07 |
EP4017593A1 (en) | 2022-06-29 |
AU2020333990B2 (en) | 2024-05-23 |
US20220332720A1 (en) | 2022-10-20 |
MX2022002152A (es) | 2022-05-18 |
IL290771A (en) | 2022-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6609631B2 (ja) | 縮合環ヘテロアリール化合物及びtrk抑制剤としての用途 | |
CN108349940B (zh) | 布鲁顿酪氨酸激酶抑制剂 | |
JP5327652B2 (ja) | 癌処理のための融合されたイミダゾール | |
KR20200138769A (ko) | Mat2A의 헤테로바이시클릭 억제제 및 암 치료를 위한 이의 사용 방법 | |
US9499551B2 (en) | Substituted pyrrolo[2,3-b]pyridines for treating cancer or inflammatory diseases | |
KR102345381B1 (ko) | 키나제 억제제로서 유용한 카르바졸 카르복스아미드 화합물 | |
CN103476768A (zh) | 6,5-杂环炔丙醇化合物及其用途 | |
KR101133959B1 (ko) | 면역조절 헤테로고리 화합물 | |
JP2010505797A (ja) | Hcv阻害剤として有用なカルボキシアミド4−[(4−ピリジル)アミノ]ピリミジン | |
JP2007501827A (ja) | キナーゼ阻害剤として活性なピリミジルピロール誘導体 | |
JP7485399B2 (ja) | インターフェロン遺伝子の刺激因子stingの単環式アゴニスト | |
TW202204344A (zh) | 酪胺酸激酶2抑制劑、其製備方法及醫藥用途 | |
JP7414965B2 (ja) | インターフェロン遺伝子の刺激因子stingの二環式アゴニスト | |
JP2022533182A (ja) | タンパク質キナーゼ阻害剤ならびに疾患および状態の治療のためのその使用 | |
CN112533924A (zh) | 作为IRAK4抑制剂的吡咯并[1,2-b]哒嗪衍生物 | |
RU2800072C1 (ru) | Бициклические агонисты стимулятора генов интерферона sting | |
RU2813691C2 (ru) | Моноциклические агонисты стимулятора генов интерферона sting | |
JP2023539526A (ja) | インターフェロン遺伝子刺激因子stingのアゴニスト | |
TW202317567A (zh) | 經取代的1H-吡唑并[4,3-c]喹啉、製備方法及其用途 | |
WO2023030215A1 (zh) | 吡啶并嘧啶酮类衍生物及其制备方法和用途 | |
JP2022541819A (ja) | Irak4阻害剤として有用なチエノピリジニルおよびチアゾロピリジニル化合物 | |
WO2022063050A1 (zh) | 吡唑类化合物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220325 Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220415 Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220425 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220325 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230214 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230329 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230627 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230922 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20231114 |
|
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: 20231204 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231228 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7414965 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |