CN117942342A - 干扰素基因刺激物sting的激动剂 - Google Patents
干扰素基因刺激物sting的激动剂 Download PDFInfo
- Publication number
- CN117942342A CN117942342A CN202311816056.XA CN202311816056A CN117942342A CN 117942342 A CN117942342 A CN 117942342A CN 202311816056 A CN202311816056 A CN 202311816056A CN 117942342 A CN117942342 A CN 117942342A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- cycloalkyl
- formula
- administering
- sting
- 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.)
- Pending
Links
- 108010050904 Interferons Proteins 0.000 title claims abstract description 19
- 239000000556 agonist Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims abstract description 11
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims abstract description 11
- 230000008685 targeting Effects 0.000 claims abstract description 11
- 230000002601 intratumoral effect Effects 0.000 claims abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 40
- -1 methylenedioxy, difluoromethylenedioxy, ethylenedioxy Chemical group 0.000 claims description 39
- 230000014509 gene expression Effects 0.000 claims description 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 239000004475 Arginine Substances 0.000 claims description 8
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 230000005865 ionizing radiation Effects 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 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
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000009885 systemic effect Effects 0.000 abstract 1
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 23
- 125000000623 heterocyclic group Chemical group 0.000 description 22
- 125000005842 heteroatom Chemical group 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 125000006413 ring segment Chemical group 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 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 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229940044665 STING agonist Drugs 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 101710118064 Cyclic GMP-AMP synthase Proteins 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 102000003996 Interferon-beta Human genes 0.000 description 4
- 108090000467 Interferon-beta Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- CRPUJAZIXJMDBK-UHFFFAOYSA-N camphene Chemical compound C1CC2C(=C)C(C)(C)C1C2 CRPUJAZIXJMDBK-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229960001388 interferon-beta Drugs 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000010512 thermal transition Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001262 western blot Methods 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
- 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
- QEDHNJSBVURTND-UHFFFAOYSA-N 6-imidazol-1-ylpyridazine-3-carboxylic acid Chemical compound N1=NC(C(=O)O)=CC=C1N1C=NC=C1 QEDHNJSBVURTND-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 2
- 108030002637 Cyclic GMP-AMP synthases Proteins 0.000 description 2
- JBZVWABPSHNPIK-UHFFFAOYSA-N Ethyl-2-amino-1-cyclohexene-1-carboxylate Chemical compound CCOC(=O)C1=C(N)CCCC1 JBZVWABPSHNPIK-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 2
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 2
- 101001082060 Homo sapiens Interferon-induced protein with tetratricopeptide repeats 3 Proteins 0.000 description 2
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 description 2
- 102000002227 Interferon Type I Human genes 0.000 description 2
- 108010014726 Interferon Type I Proteins 0.000 description 2
- 102100026720 Interferon beta Human genes 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXRCIOIWVGAZEP-UHFFFAOYSA-N Primaeres Camphenhydrat Natural products C1CC2C(O)(C)C(C)(C)C1C2 PXRCIOIWVGAZEP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229930006739 camphene Natural products 0.000 description 2
- ZYPYEBYNXWUCEA-UHFFFAOYSA-N camphenilone Natural products C1CC2C(=O)C(C)(C)C1C2 ZYPYEBYNXWUCEA-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000005879 dioxolanyl group Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 125000003427 indacenyl group Chemical group 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XIURVKGLLDXVNH-UHFFFAOYSA-N methyl 2-amino-5-fluoro-4-methoxybenzoate Chemical compound COC(=O)C1=CC(F)=C(OC)C=C1N XIURVKGLLDXVNH-UHFFFAOYSA-N 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 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
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002849 thermal shift Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- YMZPQKXPKZZSFV-CPWYAANMSA-N 2-[3-[(1r)-1-[(2s)-1-[(2s)-2-[(1r)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carbonyl]oxy-3-(3,4-dimethoxyphenyl)propyl]phenoxy]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC[C@H](C=1C=C(OCC(O)=O)C=CC=1)OC(=O)[C@H]1N(C(=O)[C@@H]([C@H]2C=CCCC2)C=2C=C(OC)C(OC)=C(OC)C=2)CCCC1 YMZPQKXPKZZSFV-CPWYAANMSA-N 0.000 description 1
- RZSONIKSTNZZNS-UHFFFAOYSA-N 6,7-difluoro-2-(6-imidazol-1-ylpyridazin-3-yl)-3H-quinazolin-4-one Chemical compound N1(C=NC=C1)C1=CC=C(N=N1)C1=NC2=CC(=C(C=C2C(N1)=O)F)F RZSONIKSTNZZNS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 102100037435 Antiviral innate immune response receptor RIG-I Human genes 0.000 description 1
- 101710127675 Antiviral innate immune response receptor RIG-I Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150031621 CGAS gene Proteins 0.000 description 1
- FVTUGYDKOFOZLB-UHFFFAOYSA-N CN(C)[C]N1CCOCC1 Chemical compound CN(C)[C]N1CCOCC1 FVTUGYDKOFOZLB-UHFFFAOYSA-N 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
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100027302 Interferon-induced protein with tetratricopeptide repeats 3 Human genes 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
- 101100043703 Mus musculus Sting1 gene Proteins 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 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
- 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
- 230000037453 T cell priming Effects 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 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 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids 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
- 238000004458 analytical method Methods 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000003828 azulenyl group Chemical group 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 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
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125898 compound 5 Drugs 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
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 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
- 238000002474 experimental method Methods 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000004547 gene signature Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 102000050022 human STING1 Human genes 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 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
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical group CC(C)C(O)=O KQNPFQTWMSNSAP-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
- 239000003446 ligand Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- FPKXYXKLOWAIOX-UHFFFAOYSA-N methyl 6-chloropyridazine-3-carboxylate Chemical compound COC(=O)C1=CC=C(Cl)N=N1 FPKXYXKLOWAIOX-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 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
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 125000005561 phenanthryl group Chemical group 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
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 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
- 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
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 239000007858 starting material 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
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/5365—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 heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further 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
- A61K31/495—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
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further 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
- A61K31/495—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
- A61K31/495—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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本申请涉及干扰素基因刺激物STING的激动剂。本发明提供了具有干扰素基因刺激物(STING)激动剂生物活性的化合物,其可用于在受肿瘤折磨的患者中治疗该肿瘤。所述化合物为如本文中所限定的式(I)化合物。用于实践本发明方法的化合物可通过经口递送进行递送用于全身性暴露,以及瘤内递送。使用式(I)化合物的抗肿瘤治疗还可包括施用有效剂量的免疫检查点靶向药物。
Description
本申请是申请日为2019年2月21日、申请号为“201980021235.X”、发明名称为“干扰素基因刺激物STING的激动剂”的中国专利申请的分案申请,原申请是国际申请PCT/US2019/018899的中国国家阶段申请。
相关申请的交叉引用
本申请要求2018年2月21日提交的美国临时申请序列No.62/633,409的优先权,其公开内容通过引用整体并入本文。
技术领域
本申请涉及干扰素基因刺激物STING的激动剂。
背景技术
cGAS-STING信号传导途径在哺乳动物宿主细胞所发动以消除多种DNA和RNA病毒的固有免疫应答中发挥关键作用。STING(干扰素基因刺激物,Stimulator of InterferonGene)是一种内质网(endoplasmic reticulum,ER)驻留信号传导蛋白,部分地定位于线粒体相关膜,其在免疫和非免疫细胞类型二者中均广泛表达。响应于环状二核苷酸(cyclicdinucleotide,CDN)(包括响应于胞质DNA通过环状GMP-AMP合酶(cyclic GMP-AMPsynthase,cGAS)产生的2’-3’cGAMP),STING转位到核周区域,在那里其以TBK1-/IRF3-依赖性的方式迅速地诱导I型干扰素(IFN)和促炎性细胞因子的产生。还已发现STING直接结合胞质DNA,尽管直接的DNA感应活性的生理相关性仍有待充分表征。
最近的工作表明,STING在针对肿瘤细胞的免疫应答中发挥必不可少的作用。在肿瘤微环境中高效的肿瘤引发的T细胞启动(T cell priming)需要通过驻留树突状细胞的干扰素-β(IFN-b)的产生,并且已示出IFN-b的表达依赖于STING途径的激活(1)。实际上,已示出瘤内递送基于核苷酸的STING激动剂诱导了在同系小鼠模型中建立的肿瘤的极大消退(1)。此外,还已示出STING途径的激活在经辐照的肿瘤微环境中通过IFN-b介导的免疫应答而显著有助于辐射的抗肿瘤作用。
发明内容
在多个实施方案中,本发明提供了干扰素基因刺激物(STING)的激动剂,其可用于治疗肿瘤。
例如,本发明可提供:刺激干扰素基因之表达的方法,其包括向患者施用有效剂量的干扰素基因刺激物(STING)的激动剂,所述激动剂包含式(I)化合物(下文);以及在患者中治疗肿瘤的方法,其包括向患者施用有效剂量的干扰素基因刺激物(STING)的激动剂,所述激动剂包含式(I)化合物或其可药用盐:
其中每个R1独立地为(C1-C4)烷基或CN,nr1为0、1、2或3,前提是每个R1与碳原子键合;并且,
AR是式-C(=O)N(R)Ar1的基团;
其中Ar1选自:
其中波浪线表示键合位置;
其中任意Ar1被nr2个独立选择的选自以下的R2基团取代:
-(C1-C4)-烷基、-(C1-C4)-烷基O、-(C1-C4)-烷基OC(O)、-CN、-卤素、-(C3-C7)环烷基、-(C1-C4)-烷基OC(O)、-COOH、(C3-C7)-环烷基OC(O)、-CN、-F、-Cl、-SF5、-亚甲二氧基、-二氟亚甲二氧基、-亚乙二氧基、-CF3、-OCF3、-C(O)NH2、-C(O)NH(CH2)2OH、-CH2OH、-NR2、-C(/)ONH-精氨酸、-C(O)O(CH2)2NR2、
其中波浪线表示键合位置;并且,nr2=0、1、2或3;
或者,
AR是下式的基团:
其中R3选自:
(C1-C4)-烷基、(C1-C4)-烷基O、(C1-C4)-烷基OC(O)、CN、卤素、(C3-C7)环烷基、(C1-C4)-烷基OC(O)、COOH、(C3-C7)-环烷基OC(O)、CN、F、Cl、-SF5、亚甲二氧基、二氟亚甲二氧基、亚乙二氧基、CF3、-OCF3、CONH2、CONH(CH2)2OH、CH2OH、NR2、CONH-精氨酸和C(O)O(CH2)2NR2;并且nr3=0、1、2或3。
更具体地,该方法可使用式(I)化合物进行,其中n1为0;或者n1为1或2并且R1是甲基。
更具体地,该方法可使用式(I)化合物进行,其中X是甲基、乙基或异丙基羧酸酯。另外地,该方法可使用式(I)化合物进行,其中X是1,1,1,3,3,3-六氟丙烷-2-醇-2-基基团。另外地,该方法可使用式(I)化合物进行,其中Ar为苯基。另外地,该方法可使用式(I)化合物进行,另外地,该方法可使用式(I)化合物进行,其中R2独立地选自氟、氯、(C1-C4)烷基、三氟甲基或氰基,并且n2为1或2;或者两个R2一起形成亚甲二氧基。
此外,本发明的方法可使用有效剂量的本申请中公开的任一种具体化合物来进行;参见,例如,表1、2和5。
在多个实施方案中,治疗肿瘤的方法还可包括通过经口施用或瘤内施用或者这二者来施用有效剂量的式(I)化合物或本文中公开的任一种具体化合物。
在多个实施方案中,治疗肿瘤的方法还可包括施用有效剂量的式(I)化合物或本文中公开的任一种具体化合物,其中施用包括向患者施用作为抗体-药物缀合物或在脂质体制剂中的化合物。
在多个实施方案中,治疗肿瘤的方法还可包括施用有效剂量的式(I)化合物或本文中公开的任一种具体化合物,还包括施用有效剂量的免疫检查点靶向药物。例如,免疫检查点靶向药物可以是抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体或抗4-1BB抗体。
在多个实施方案中,治疗肿瘤的方法还可包括施用有效剂量的式(I)化合物或本文中公开的任一种具体化合物,还包括施用电离辐射或抗癌药物。
本发明还可包含本文中公开和要求保护的新的式(I)化合物。
附图说明
图1:
用提高剂量的2’3’-cGAMP处理野生型和STING KO THP-1ISRE-萤光素酶报道分子细胞,并在处理之后48小时评估报道分子活性(发光)(A)。通过Western印迹在γ-微管蛋白用作蛋白质加载对照的情况下证实STING KO THP-1细胞中STING蛋白表达的缺乏(B)。用提高剂量的化合物164(Cmpd 164)处理野生型和STING KO THP-1报道分子细胞,并在处理之后24小时评估报道分子活性和细胞生存力(C至D)。
图2:
用poly(dA:dT)(其是RIG-I依赖性信号传导级联和cGAS依赖性信号传导级联二者的已知激活剂)刺激野生型和STING KO THP-1细胞,并在48小时之后通过qPCR评估下游靶基因的表达(A)。用指定剂量的2’3’-cGAMP或Cmpd 164刺激野生型和STING KO THP-1细胞,并通过IFNB1(B)以及干扰素刺激基因IFIT3(C)和CXCL10(D)的基因表达分析来评估I型干扰素信号传导的激活。
图3:
将人STING蛋白的c端结构域(第138至379位氨基酸)用2’3’-cGAMP[100μM](A)或Cmpd 181[100μM](B)和1×荧光染料进行孵育,然后暴露于提高的温度。使用导数法计算解链温度(Tm),并通过相对于合适的载剂对照(C)进行归一化来获得由配体结合引起的解链温度的变化(ΔTm)。
具体实施方式
对于开发STING途径激动剂以用于多种免疫肿瘤学应用有极大兴趣。最值得注意地,STING途径激动剂作为涉及免疫检查点靶向药物的组合治疗的一部分,在未能响应于单独的检查点阻断(blockade)的患者中具有重要的潜在应用。
我们建立了一个稳健的平台,用于识别非核苷酸小分子STING激动剂。这是使用涉及人THP-1细胞系的初步测定来建立的,该细胞系携带具有5个IFN信号传导应答元件拷贝的IRF诱导型报道分子。使用计数器筛选来消除萤光素酶伪影(artifact)并确保人-啮齿动物的跨物种反应性以及途径选择性,该计数器筛选涉及可替代的报道分子构建体、基于啮齿动物细胞的测定法以及cGAS和STING敲除细胞系。使用生化测定法来鉴定所识别的命中(hit)的特定靶标,该生化测定法涉及cGAS酶促活性和STING蛋白结合测定。迄今为止,从约100,000种化合物的初步筛选中,我们已经鉴定出至少一种新的高度易处理的真实STING激动剂支架化合物164,表1(EC50为约1μM,表1),其以与对于2’-3’cGAMP所观测到的效力相当的效力诱导相关细胞类型中的干扰素刺激基因标签表达和人PBMC中的I型IFN蛋白表达。表1化合物164在野生型和cGAS敲除细胞中所观测到的活性以及在STING敲除细胞中所观测到的活性缺乏,提供了该化合物系列通过直接用作STING激动剂而发挥作用的证据。STING蛋白的热转变数据提供了另外的证据。涉及该系列中约100种类似物的设计、合成和测试的初步药物化学工作,确定了活性所需的分子关键特征,并使得鉴定出基于细胞的效力提高约10倍(通过例如调整苯胺环上的取代模式)和血浆稳定性提高约50倍(通过调整酯的取代基的大小)的衍生物。
在本文中含义内的“治疗”是指缓解与病症或疾病相关的症状,或者抑制这些症状的进一步发展或恶化,或者防止或预防疾病或病症,或者治愈疾病或病症。类似地,如本文中所用,本发明化合物的“有效量”或“治疗有效量”是指化合物完全或部分地缓解与障碍或病症相关的症状,或者停止或减缓这些症状的进一步发展或恶化,或者防止障碍或病症或提供对障碍或病症的预防的量。特别地,“治疗有效量”是指在必要的剂量下和必要的时间段内有效以实现期望的治疗结果的量。治疗有效量也是其中本发明化合物的治疗有益作用超过任何毒性或有害作用的量。
当用于描述患有病症的个体的治疗时,表述“有效量”是指有效地抑制或者以其他方式作用于个体组织中的STING(其中STING参与该病症)的本发明化合物的量或浓度,其中这样的抑制或其他作用发生的程度足以产生有益的治疗效果。
术语“可药用盐”是指无毒的无机或有机酸和/或碱加成盐,参见,例如,Lit etal.,Salt Selection for Basic Drugs(1986),Int J.Pharm.,33,201-217,其通过引用并入本文。
使用例如本领域公知的化学基团的标准缩写;例如,Me=甲基,Et=乙基,i-Pr=异丙基,Bu=丁基,t-Bu=叔丁基,Ph=苯基,Bn=苄基,Ac=乙酰基,Bz=苯甲酰基等。
除非另有说明,否则术语“卤代”或“卤素”或“卤化物”本身或者作为另一取代基的一部分意指氟、氯、溴或碘原子,优选氟、氯或溴。
“卤代烷基”包括单卤代烷基;多卤代烷基,其中所有卤代原子可以是相同的或不同的;以及全卤代烷基,其中所有氢原子被相同或不同的卤素原子,例如氟和/或氯原子取代。卤代烷基的一些实例包括三氟甲基、1,1-二氯乙基、1,2-二氯乙基、1,3-二溴-3,3-二氟丙基、全氟丁基等。
芳基是在环中不包含杂原子的环状芳香烃。如本领域所公知的,芳族化合物是包含4n+2π个电子的多不饱和环状体系,其中n是整数。因此,芳基包括但不限于:苯基、薁基、庚搭烯基(heptalenyl)、联苯基、引达省基(indacenyl)、芴基、菲基(phenanthrenyl)、三亚苯基(triphenylenyl)、芘基、并四苯基、基、亚联苯基、蒽基和萘基。在一些实施方案中,芳基在基团的环部分中包含约6至约14个碳。如上所限定,芳基可以是未经取代的或经取代的。代表性的经取代芳基可以是经单取代的或经取代多于一次的,例如但不限于经2-、3-、4-、5-或6-取代苯基或经2至8取代萘基,其可被碳或非碳基团例如上面列出的那些取代。
杂环基基团或术语“杂环基”包括包含3个或更多个环原子的芳族和非芳族环化合物,其中一个或更多个环原子是杂原子,例如但不限于N、O和S。因此杂环基可以是环杂烷基或杂芳基,或者如果是多环的话,则可以是其任意组合。在一些实施方案中,杂环基包含3至约20个环原子,而另一些这样的基团具有3至约15个环原子。表示为C2-杂环基的杂环基可以是具有两个碳原子和三个杂原子的5-环、具有两个碳原子和四个杂原子的6-环等。同样地,C4-杂环基可以是具有一个杂原子的5-环、具有两个杂原子的6-环等。碳原子数加上杂原子数的和等于环原子总数。环的大小也可由计算了碳和非碳环原子二者的环中原子总数表示,例如3至10元杂环基。杂环基环还可包含一个或更多个双键。杂芳基环是杂环基的一个实施方案。术语“杂环基”包括稠环物类,其包括包含稠合的芳族和非芳族基团的那些。例如,二氧戊环基环和苯并二氧戊环基环体系(亚甲基二氧苯基环体系)二者均为本文中含义内的杂环基。该术语还包括含有一个或更多个杂原子的多环例如双环和三环体系,例如但不限于奎宁环基(quinuclidyl)。杂环基可以是未经取代的或者可以是经取代的。
杂芳基是含有5个或更多个环原子的杂环芳族环化合物,环原子中的一个或更多个是杂原子,例如但不限于N、O和S;例如,杂芳基环可具有5至约8至12个环原子。杂芳基是具有芳族电子结构的多种杂环基,其是包含4n+2π个电子的多不饱和环状体系,其中n是整数。表示为C2-杂芳基的杂芳基可以是具有两个碳原子和三个杂原子的5-环(即5元环)、具有两个碳原子和四个杂原子的6-环(即6元环)等。同样地,C4-杂芳基可以是具有一个杂原子的5-环、具有两个杂原子的6-环等。碳原子数加上杂原子数的和等于环原子总数。
本文中所述的杂芳基环体系的一些实例包括式的结构单元,咪唑基-哒嗪,知晓其还可被描绘为/>在此描述的另一个杂芳基环体系具有式/>知晓其还可被描绘为/>类似地,本文中所述的另一些芳基(例如,苯基)和杂芳基(例如,吡啶基)环体系可以用明确的双键或者用芳基“环”命名法(aryl“circle”nomenclature)来书写,但是其含义是相同的。
环烷基是包含一个或更多个碳环的基团,包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在一些实施方案中,环烷基可具有3至约8至12个环原子,而在另一些实施方案中,环碳原子数为3至4、5、6或7。环烷基还包括多环环烷基,例如但不限于降冰片基、金刚烷基、冰片基、莰烯基、异莰烯基和蒈烯基,以及稠环,例如但不限于萘烷基等。环烷基还包括被如上限定的直链或支链烷基取代的环。
环烯基包括在两个碳之间具有至少一个双键的环烷基。因此例如,环烯基包括但不限于环己烯基、环戊烯基和环己二烯基。环烯基可具有3至约8至12个环原子,而在另一些实施方案中,环碳原子数为3至5、6或7。环烷基还包括多环环烷基,例如但不限于降冰片基、金刚烷基、冰片基、莰烯基、异莰烯基和蒈烯基,以及稠环,例如但不限于萘烷基等,前提是它们在环中包含至少一个双键。环烯基还包括被如上限定的直链或支链烷基取代的环。
杂环基基团或术语“杂环基”包括包含3个或更多个环原子的芳族和非芳族环化合物,其中一个或更多个环原子是杂原子,例如但不限于N、O和S。因此杂环基可以是环杂烷基或杂芳基,或者如果是多环的话,则可以是其任意组合。在一些实施方案中,杂环基包含3至约20个环原子,而另一些这样的基团具有3至约15个环原子。表示为C2-杂环基的杂环基可以是具有两个碳原子和三个杂原子的5-环、具有两个碳原子和四个杂原子的6-环等。同样地,C4-杂环基可以是具有一个杂原子的5-环、具有两个杂原子的6-环等。碳原子数加上杂原子数的和等于环原子总数。环的大小也可由计算了碳和非碳环原子二者的环中原子总数表示,例如3至10元杂环基。杂环基环还可包含一个或更多个双键。杂芳基环是杂环基的一个实施方案。术语“杂环基”包括稠环物类,其包括包含稠合的芳族和非芳族基团的那些。例如,二氧戊环基环和苯并二氧戊环基环体系(亚甲基二氧苯基环体系)二者均为本文中含义内的杂环基。该术语还包括含有一个或更多个杂原子的多环例如双环和三环体系,例如但不限于奎宁环基。
表1:结构、生物活性和支持结构的数据
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
相关文献
[1]Corrales L,Glickman LH,McWhirter SM,Kanne DB,Sivick KE,Katibah GE,Woo SR,Lemmens E,Banda T,Leong JJ,Metchette K,Dubensky TW Jr,Gajewski TF.(2015)Direct Activation of STING in the Tumor Microenvironment Leads toPotent and Systemic Tumor Regression and lmmunity.Cell Rep.11:1018-30.
[2]Deng,L.et al.(2014)STING-Dependent Cytosolic DNA Sensing PromotesRadiation-Induced Type I Interferon-DependentAntitumor Immunity inImmunogenic Tumors,Immunity.41:843.
[3]Corrales L,Matson V,Flood B,Spranger S,Gajewski TF.(2017)Innateimmune signaling and regulation in cancer immunotherapy.Cell Res.27:96-108.
[4]Corrales L,McWhirter SM,Dubensky TW Jr,Gajewski TF.(2016)The hostSTING pathway at the interface of cancer and immunity.J Clin Invest.126:2404-11.
关于包括施用本发明化合物和免疫检查点靶向药物的组合治疗,或者用于增强基于电离辐射的和现有的化学治疗治疗性方法(例如基于DNA损伤的化学治疗)的组合治疗,我们认为本发明的STING激动剂可补充并增强这些已知治疗方法的效果。这是基于最近的论文,其表明使用这些方法的STING依赖性微核介导的肿瘤清除的关键作用,参见例如:
[5]Mackenzie,K.F.,et all,(2017),cGAS surveillance of micronucleilinks genome instability to innate immunity,Nature,548,461.
[6]Wang,W.et al.,(2016),Effector T Cells Abrogate Stroma-MediatedChemoresistance in Ovarian Cancer,Cell,165,1092-1105.
[7]Charlotte E.Ariyan,et al.,January 16,2018;DOI:10.1158/2326-6066,Robust antitumor responses result from local chemotherapy and CTLA-4blockade,cancerimmunolres.aacrjournals.org on January 31,2018.
[8]Chung Kil Song,et al.,www.moleculartherapy.org vol.15 no.8aug.2007,Chemotherapy Enhances CD8+ T Cell-mediated Antitumor Immunitylnduced by Vaccination With Vaccinia Virus.
本发明的化合物可用于与施用有效剂量的免疫检查点靶向药物的治疗组合中。例如,免疫检查点靶向药物可以是抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体或抗4-1BB抗体。参见,例如:
[9]Ager,CR,et al.,(2017)Cancer Immunol Res;5(8),676.
[10]Fu,J.et al.(2015)Sci Transl Med.2015April 15;7(283):283ra52.doi:10.1126/scitranslmed.aaa4306.
[11]Wang,H.,et al.(2017)PNAS|February 14,2017|vol.114|no.7|1637-1642.
实施例
组织培养
野生型(cat.no.thpl-isg)和STING KO(cat.no.thpd-kostg)THP-1-Lucia ISG细胞购自Invivogen,并保持在除非另有说明否则由以下构成的生长培养基中:RPMI 1640、2mM L-谷氨酰胺、25mM HEPES、10%热灭活胎牛血清(fetal bovine serum,FBS)、1,000单位/ml青霉素、1,000μg/ml链霉素、0.25μg/ml两性霉素B和100μg/ml吉欧霉素(zeocin)。
1型干扰素刺激
Poly(dA:dT)和2’3’-cGAMP购自invivogen,并根据制造商的说明书进行重悬。
ISRE-萤光素酶测定法
将THP-1 Lucia ISG细胞以5×105个细胞/ml的密度重悬于低血清生长培养基(2%FBS)中,并用测试物品或载剂(DMSO)处理。将50μL细胞接种到384孔白色葛莱娜板(greiner plate)的每个孔中,并孵育24小时。为了评价萤光素酶报道分子的表达,向每个孔添加30μl Quanti-luc(Invivogen)检测试剂,并使用积分时间设置为0.1秒的Envision读板仪(Perkin Elmer)来读取发光。
生存力测定
将细胞以5×105个细胞/ml的密度重悬于低血清生长培养基中,并用测试物品或载剂(DMSO)处理。将50μL细胞接种到384孔白色葛莱娜板的每个孔中,并孵育24小时。为了评价萤光素酶报道分子的表达,向每个孔添加30μl CellTiter-Glo(Promega)检测试剂,并使用积分时间设置为0.1秒的Envision读板仪来检测发光。
Western印迹
将细胞溶解在新鲜添加了蛋白酶和磷酸酶抑制剂(Cell Signaling)的1×蛋白质裂解缓冲液(25mM HEPES、pH 7.4、300mM NaCl、1.5mM MgCl2、1mM EGTA、1%P-40、1%脱氧胆酸钠、2.5mM焦磷酸钠、1mM甘油磷酸)中。使用BoltTM4%至12%Bis-Tris凝胶和BoltTM微型转移系统遵循制造商的说明书(ThermoFisher Scientific)进行Western印迹。STING和γ-微管蛋白抗体购自Cell Signaling,将其稀释在5%BSA、1×TBS-T缓冲液中(表3)。将抗兔HRP抗体稀释在5%脱脂干乳、1×TBS-T缓冲液中,并使用ChemiDoc Imager(BioRad)对发光信号进行成像。
半定量实时PCR(qPCR)
将THP-1细胞以5×105个细胞/ml的密度重悬于低血清生长培养基中,并用测试物品或载剂(DMSO)处理。将2.5mL细胞接种到6孔板的每个孔中,并孵育24小时。使用RNeasyPlus微型试剂盒(RNeasy Plus Mini Kit)(Qiagen)分离RNA,并使1μg经纯化的RNA反转录成cDNA(VILO,cat.no.11755050,ThermoFisher Scientific)。用Taqman Universal MixII(cat.no.4440038,ThermoFisher)使用表4中列出的Taqman引物和探针遵循制造商的说明书来评估基因表达。基因表达使用双ΔCt法来归一化,并以表达倍数变化进行报告。
STING热转变分析(Thermal Shift Assay,TSA)
如先前所详细描述的(Ouyang et al.,2012),表达人和小鼠STING的c端结构域(c-terminal domain,CTD)并进行纯化。向在1×蛋白质热转变缓冲液(在蛋白质热转变染料试剂盒(Protein Thermal Shift Dye Kit)(cat#4461146,ThermoFisher Scientific)中提供)中的稀释的STING蛋白(0.22mg/ml)添加测试物品或载剂对照。添加热转变染料并进行混合,然后根据针对染料试剂盒所概述的参数进行解链曲线。解链温度(Tm)使用蛋白质热转变软件(Protein Thermal Shift Software)v1.3(cat#4466038,ThermoFisherScientific)使用导数法来计算。
表2:Cell Signaling的抗体
蛋白质靶标 | Cat.No. | 稀释 |
STING | 13647 | 1∶1000 |
γ-微管蛋白 | 5886 | 1∶3000 |
兔IgG | 7074 | 1∶3000 |
表3:ThermoFisher Scientific Taqman引物/探针
基因符号 | 物种 | Cat.No. | 染料 |
IFNB1 | 人 | Hs01077958_s1 | FAM |
CXCL10 | 人 | Hs00171042_m1 | FAM |
IFIT3 | 人 | Hs01922752_s1 | FAM |
B2M | 人 | Hs00187842_m1 | VIC |
Ouyang,S.,Song,X.,Wang,Y.,Ru,H.,Shaw,N.,Jiang,Y.,Niu,F.,Zhu,Y.,Qiu,W.,Parvatiyar,K.,et al(2012).Structural analysis of the STING adaptor proteinreveals a hydrophobic dimer interface and mode of cyclic di-GMPbinding.Immunity 36,1073-1086.
可用于实施本发明方法的化合物可根据以下方法、结合有机合成的普通知识和技能、替换合适的试剂(如对从业者而言明显的)来制备。
实验方法
缩写
使用以下缩写:四氢呋喃(THF),二氯甲烷(DCM),N,N-二甲基甲酰胺(DMF),二甲基乙酰胺(DMA),二甲基亚砜(DMSO),三氟乙酸(TFA),三乙胺(TEA),二异丙基乙胺(DIPEA),(1-氰基-2-乙氧基-2-氧代亚乙基氨基氧基)二甲基氨基-吗啉代-碳六氟磷酸盐(COMU),1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶/>3-氧化物六氟磷酸盐、N-[(二甲基氨基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亚甲基]-N-甲基甲酰胺六氟磷酸盐N-氧化物(HATU)。
本发明化合物制备的一些通用实施例
本发明化合物的起始物质和中间体可通过例如以下描述的方法的应用或改变形式、或其明显的化学等同方案来制备,如在文献例如The Science of Synthesis,Volumes1-8.Editors E.M.Carreira et al.Thieme publishers(2001-2008)中所述。还可使用商业计算机搜索引擎,例如Scifinder(www.cas.org)或Reaxys(www.reaxys.com),通过对结构和反应的搜索来获得试剂和反应方案的详情。
部分I:中间体的制备
方案1:中间体A的合成:
6-(1H-咪唑-1-基)哒嗪-3-羧酸,A:向甲基6-氯哒嗪-3-羧酸酯(1g,5.8mmol)和咪唑(400mg,5.8mmol)在无水DMF(10mL)中的悬浮液中添加K2CO3(950mg,6.8mmol),并将反应混合物在120℃下搅拌3小时。通过LCMS监测反应。在完全转化为甲基6-(1H-咪唑-1-基)哒嗪-3-羧酸酯之后,向反应混合物中添加2.5M aq.LiOH(2.8mL,6.96mmol),并在60℃下搅拌1小时。通过LCMS监测反应。反应完成之后,将反应混合物用aq.1M HCl酸化,并将所得沉淀物过滤并用水洗涤,以获得作为灰白色固体的酸A(720mg),其无需进一步纯化即用于下一步骤。LC-MS(ESI+):m/z 191.0[M+H]+。
部分II:示例化合物的制备
所有化合物均使用以下例示的方法来制备。
实施例1
方案2:化合物1的合成:
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)苯甲酸甲酯,1:将中间体A(190mg,1mmol)、2-氨基苯甲酸甲酯(166mg,1.1mmol)、HATU(456mg,1.2mmol)和DIPEA(0.52mL,3mmol)溶解在DMF(5mL)中,并在室温下搅拌过夜。反应完成之后,将溶剂在减压下蒸发并将所得粗制物质通过硅胶柱色谱法使用DCM中的2%至5%MeOH进行纯化,以获得作为灰白色固体的化合物1(226mg)。LC-MS(ESI+):m/z 324.27[M+H]+。
方案3
a试剂和条件:a)亚硫酰氯,回流,3小时;2-氨基环己-1-烯-1-羧酸乙酯,DIPEA,乙腈,rt,30分钟
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)环己-1-烯-1-羧酸乙酯:将6-(1H-咪唑-1-基)哒嗪-3-羧酸(19mg,0.1mmol)溶解在0.3mL亚硫酰氯中,并将混合物在回流下加热3小时。然后,在真空下除去过量的亚硫酰。将固体溶解在0.5mL无水乙腈中,并在室温下添加2-氨基环己-1-烯-1-羧酸乙酯(16.9mg,0.1mmol)和DIPEA(26.1μL,0.15mmol)在0.5mL无水乙腈中的溶液。搅拌30分钟之后,将粗制混合物过滤并通过制备型HPLC进行纯化,以得到产物(6.8mg,20%产率)。
方案4:化合物8的合成:
/>
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-5-氟-4-甲氧基苯甲酸甲酯,8:将中间体A(190mg,1mmol)在SOCl2(5mL)的存在下在80℃下搅拌2小时。然后除去挥发物,随后添加2-氨基-5-氟-4-甲氧基苯甲酸甲酯(219mg,1.1mmol)和DIPEA(0.52mL,3mmol)在乙腈(5mL)中的溶液。将所得反应混合物在室温下搅拌1小时。通过LCMS监测反应。反应完成之后,除去溶剂,并将所得粗制物质通过硅胶柱色谱法使用DCM中的2%至5%MeOH进行纯化,以获得作为灰白色固体的化合物8(223mg)。LC-MS(ESI+):m/z 372.1[M+H]+。
实施例2-Li
方案5:化合物2-Li的合成
/>
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-5-甲氧基苯甲酸锂,2-Li:通过使用化合物1所遵循的方法(方案C)制备2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-5-甲氧基苯甲酸甲酯。将所得酯(20mg,0.057mmol)溶解在DMSO(0.8mL)中,然后添加aq.0.1M LiOH(0.68mL,1.2mmol),随后在室温下搅拌直至反应完成(约3小时)。通过LCMS监测反应。然后,将反应混合物通过逐滴添加1M HCl酸化以产生期望的酸。将所获得的沉淀物分离并用水洗涤,以得到作为灰白色固体的酸2。LC-MS(ESI+):m/z340.4[M+H]+。将酸2(10.2mg,0.03mmol)另外地混悬在2.5mL水中(0.25mL/mg),并进行声处理20分钟以制备均匀的混悬液。此后,添加1MLiOH(30μL,0.03mmol)以获得澄清的锂盐溶液,然后将其过滤以除去任何不溶性颗粒。将所得溶液冻干以获得相应的锂盐2-Li。LC-MS(ESI+):m/z 340.4[M+H]+。
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-4,5-二氟苯甲酸甲酯,5:通过使用化合物1所遵循的方法(方案C)制备化合物5。LC-MS(ESI+):m/z 360.21[M+H]+。
实施例6-Li
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-4,5-二氟苯甲酸锂,6-Li:通过使用化合物2-Li所遵循的方法(方案D)制备化合物6-Li。LC-MS(ESI+):m/z 346.1[M+H]+。
实施例7-Li
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-4-氟-5-甲基苯甲酸锂,7-Li:通过使用化合物2-Li所遵循的方法(方案D)制备化合物7-Li。LC-MS(ESI+):m/z 342.11[M+H]+。
实施例8
方案F:化合物8的合成:
2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-5-氟-4-甲氧基苯甲酸甲酯,8:将中间体A(190mg,1mmol)在SOCl2(5mL)的存在下在80℃下搅拌2小时。然后除去挥发物,随后添加2-氨基-5-氟-4-甲氧基苯甲酸甲酯(219mg,1.1mmol)和DIPEA(0.52mL,3mmol)在乙腈(5mL)中的溶液。将所得反应混合物在室温下搅拌1小时。通过LCMS监测反应。反应完成之后,除去溶剂,并将所得粗制物质通过硅胶柱色谱法使用DCM中的2%至5%MeOH进行纯化,以获得作为灰白色固体的化合物8(223mg)。LC-MS(ESI+):m/z 372.1[M+H]+。
方案G:二甲基嗪酮化合物的合成
a试剂和条件:a)亚硫酰氯,回流,3小时;DIPEA,乙腈,rt,30分钟
2-(6-(1H-咪唑-1-基)哒嗪-3-基)-6,7-二甲基-4H-苯并[d][1,3]嗪-4-酮:将2-(6-(1H-咪唑-1-基)哒嗪-3-酰氨基)-4,5-二甲基苯甲酸(33.7mg,0.1mmol)溶解在0.3mL亚硫酰氯中,并将混合物在回流下加热3小时。然后,在真空下除去过量的亚硫酰。将固体溶解在0.5mL无水乙腈中,并在室温下添加DIPEA(26.1μL,0.15mmol)在0.5mL无水乙腈中的溶液。搅拌30分钟之后,将所获得的沉淀物分离并用乙腈洗涤,以得到产物(26.2mg,82%产率)。
方案H:二氟嗪酮化合物的合成
a试剂和条件:a)甲酰胺,微波,200℃
2-(6-(1H-咪唑-1-基)哒嗪-3-基)-6,7-二氟喹唑啉-4(3H)-酮:将2-(6-(1H-咪唑-1-基)哒嗪-3-基)-6,7-二氟-4H-苯并[d][1,3]嗪-4-酮(32.7mg,0.1mmol)在2mL甲酰胺中的溶液置于10mL微波瓶(microwave vial)中,将其密封并在200℃的温度下辐照15分钟。通过LCMS监测反应。反应完成之后,添加4mL甲醇,将粗制混合物过滤并通过制备型HPLC进行纯化,以得到产物(13.0mg,40%产率)。
尽管已经以对本领域技术人员制造和使用本发明来说足够详细的方式描述和例示了本发明,但是在不脱离权利要求书的精神和范围的情况下,多种替代、修改和改进对于本领域技术人员是明显的。
本文中提及的所有专利和出版物都以相同的程度通过引用并入本文,如同每个单独的出版物均明确地和单独地表明通过引用整体并入。
Claims (16)
1.刺激干扰素基因之表达的方法,其包括向患者施用有效剂量的干扰素基因刺激物(STING)的激动剂,所述激动剂包含式(I)化合物或其可药用盐:
其中每个R1独立地为(C1-C4)烷基或CN,nr1为0、1、2或3,前提是每个R1与碳原子键合;并且,
AR是式-C(=O)N(R)Ar1的基团;R是H或(C1-C4)烷基;
其中Ar1选自:
其中波浪线表示键合位置;
其中任意Ar1被nr2个独立选择的选自以下的R2基团取代:
-(C1-C4)-烷基、-(C1-C4)-烷基O、-(C1-C4)-烷基OC(O)、-CN、-卤素、-(C3-C7)环烷基、-(C1-C4)-烷基OC(O)、-COOH、(C3-C7)-环烷基OC(O)、-SF5、-亚甲二氧基、-二氟亚甲二氧基、-亚乙二氧基、-CF3、-OCF3、-C(O)NH2、-C(O)NH(CH2)2OH、-CH2OH、-NR2、-C(/)ONH-精氨酸、-C(O)O(CH2)2NR2、
其中波浪线表示键合位置;并且,nr2=0、1、2或3;
或者,
AR是下式的基团:
其中R3选自:
(C1-C4)-烷基、(C1-C4)-烷基O、(C1-C4)-烷基OC(O)、CN、卤素、(C3-C7)环烷基、(C1-C4)-烷基OC(O)、COOH、(C3-C7)-环烷基OC(O)、-SF5、亚甲二氧基、二氟亚甲二氧基、亚乙二氧基、CF3、-OCF3、CONH2、CONH(CH2)2OH、CH2OH、NR2、CONH-精氨酸和C(O)O(CH2)2NR2;并且nr3=0、1、2或3。
2.权利要求1所述的方法,其中施用包括经口施用或瘤内施用,或者这二者。
3.权利要求1所述的方法,其中施用包括作为抗体-药物缀合物或在脂质体制剂中向所述患者施用。
4.权利要求1所述的方法,其还包括施用有效剂量的免疫检查点靶向药物。
5.权利要求4所述的方法,其中所述免疫检查点靶向药物包含抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体或抗4-1BB抗体。
6.权利要求1所述的方法,其还包括施用电离辐射或抗癌药物。
7.权利要求1所述的方法,其中所述化合物是下式中的任一种或其可药用盐:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
8.在患者中治疗肿瘤的方法,其包括向所述患者施用有效剂量的干扰素基因刺激物(STING)的激动剂,所述激动剂包含式(I)化合物或其可药用盐:
其中每个R1独立地为(C1-C4)烷基或CN,nr1为0、1、2或3,前提是每个R1与碳原子键合;并且,
AR是式-C(=O)N(R)Ar1的基团;R是H或(C1-C4)烷基;
其中Ar1选自:
其中波浪线表示键合位置;
其中任意Ar1被nr2个独立选择的选自以下的R2基团取代:
-(C1-C4)-烷基、-(C1-C4)-烷基O、-(C1-C4)-烷基OC(O)、-CN、-卤素、-(C3-C7)环烷基、-(C1-C4)-烷基OC(O)、-COOH、(C3-C7)-环烷基OC(O)、-SF5、-亚甲二氧基、-二氟亚甲二氧基、-亚乙二氧基、-CF3、-OCF3、-C(O)NH2、-C(O)NH(CH2)2OH、-CH2OH、-NR2、-C(/)ONH-精氨酸、-C(O)O(CH2)2NR2、
其中波浪线表示键合位置;并且,nr2=0、1、2或3;
或者,
AR是下式的基团:
其中R3选自:
(C1-C4)-烷基、(C1-C4)-烷基O、(C1-C4)-烷基OC(O)、CN、卤素、(C3-C7)环烷基、(C1-C4)-烷基OC(O)、COOH、(C3-C7)-环烷基OC(O)、-SF5、亚甲二氧基、二氟亚甲二氧基、亚乙二氧基、CF3、-OCF3、CONH2、CONH(CH2)2OH、CH2OH、NR2、CONH-精氨酸和C(O)O(CH2)2NR2;并且nr3=0、1、2或3。
9.权利要求8所述的方法,其中施用包括经口施用或瘤内施用,或者这二者。
10.权利要求8所述的方法,其中施用包括作为抗体-药物缀合物或在脂质体制剂中向所述患者施用。
11.权利要求8所述的方法,其还包括施用有效剂量的免疫检查点靶向药物。
12.权利要求11所述的方法,其中所述免疫检查点靶向药物包含抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体或抗4-1BB抗体。
13.权利要求8所述的方法,其还包括施用电离辐射或抗癌药物。
14.权利要求8所述的方法,其中所述化合物是下式中的任一种或其可药用盐:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
15.式(I)化合物或其可药用盐:
其中每个R1独立地为(C1-C4)烷基或CN,nr1为0、1、2或3,前提是每个R1与碳原子键合;并且,
AR是式-C(=O)N(R)Ar1的基团;R是H或(C1-C4)烷基;
其中Ar1选自:
其中波浪线表示键合位置;
其中任意Ar1被nr2个独立选择的选自以下的R2基团取代:
-(C1-C4)-烷基、-(C1-C4)-烷基O、-(C1-C4)-烷基OC(O)、-CN、-卤素、-(C3-C7)环烷基、-(C1-C4)-烷基OC(O)、-COOH、(C3-C7)-环烷基OC(O)、-SF5、-亚甲二氧基、-二氟亚甲二氧基、-亚乙二氧基、-CF3、-OCF3、-C(O)NH2、-C(O)NH(CH2)2OH、-CH2OH、-NR2、-C(/)ONH-精氨酸、-C(O)O(CH2)2NR2、
/>
其中波浪线表示键合位置;并且,nr2=0、1、2或3;
或者,
AR是下式的基团:
其中R3选自:
(C1-C4)-烷基、(C1-C4)-烷基O、(C1-C4)-烷基OC(O)、CN、卤素、(C3-C7)环烷基、(C1-C4)-烷基OC(O)、COOH、(C3-C7)-环烷基OC(O)、-SF5、亚甲二氧基、二氟亚甲二氧基、亚乙二氧基、CF3、-OCF3、CONH2、CONH(CH2)2OH、CH2OH、NR2、CONH-精氨酸和C(O)O(CH2)2NR2;并且nr3=0、1、2或3。
16.化合物,其是下式中的任一种或其可药用盐:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862633409P | 2018-02-21 | 2018-02-21 | |
US62/633,409 | 2018-02-21 | ||
PCT/US2019/018899 WO2019165032A1 (en) | 2018-02-21 | 2019-02-21 | Agonists of stimulator of interferon genes sting |
CN201980021235.XA CN111971045B (zh) | 2018-02-21 | 2019-02-21 | 干扰素基因刺激物sting的激动剂 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980021235.XA Division CN111971045B (zh) | 2018-02-21 | 2019-02-21 | 干扰素基因刺激物sting的激动剂 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117942342A true CN117942342A (zh) | 2024-04-30 |
Family
ID=67687383
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311816056.XA Pending CN117942342A (zh) | 2018-02-21 | 2019-02-21 | 干扰素基因刺激物sting的激动剂 |
CN201980021235.XA Active CN111971045B (zh) | 2018-02-21 | 2019-02-21 | 干扰素基因刺激物sting的激动剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980021235.XA Active CN111971045B (zh) | 2018-02-21 | 2019-02-21 | 干扰素基因刺激物sting的激动剂 |
Country Status (10)
Country | Link |
---|---|
US (1) | US11701364B2 (zh) |
EP (1) | EP3755331A4 (zh) |
JP (2) | JP7104999B2 (zh) |
KR (1) | KR20200123179A (zh) |
CN (2) | CN117942342A (zh) |
AU (1) | AU2019225919B2 (zh) |
CA (1) | CA3091670C (zh) |
IL (1) | IL276844A (zh) |
MX (1) | MX2020008771A (zh) |
WO (1) | WO2019165032A1 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3675859A4 (en) | 2017-08-31 | 2021-06-30 | Sperovie Biosciences, Inc. | COMPOUNDS, COMPOSITIONS AND PROCEDURES FOR TREATMENT OF DISEASES |
US11701364B2 (en) | 2018-02-21 | 2023-07-18 | The Scripps Research Institute | Agonists of stimulator of interferon genes sting |
GB201807924D0 (en) | 2018-05-16 | 2018-06-27 | Ctxt Pty Ltd | Compounds |
EP3937943A4 (en) * | 2019-03-15 | 2022-12-07 | The General Hospital Corporation | NEW SMALL MOLECULE INHIBITORS OF TEAD TRANSCRIPTION FACTORS |
AU2020333990B2 (en) * | 2019-08-21 | 2024-05-23 | The Scripps Research Institute | Bicyclic agonists of stimulator of interferon genes sting |
KR20220066277A (ko) * | 2019-08-21 | 2022-05-24 | 더 스크립스 리서치 인스티튜트 | 인터페론 유전자의 자극인자 sting의 모노시클릭 효능제 |
US20230032101A1 (en) * | 2019-10-28 | 2023-02-02 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Five-membered heterocyclic oxocarboxylic acid compound and medical use thereof |
KR20220167275A (ko) | 2020-04-10 | 2022-12-20 | 오노 야꾸힝 고교 가부시키가이샤 | 암 치료 방법 |
MX2022014110A (es) | 2020-05-15 | 2023-01-30 | Immunesensor Therapeutics Inc | Tratamientos combinados de agonistas de sting con inhibidores de puntos de control inmunitario. |
AU2021338438A1 (en) * | 2020-09-02 | 2023-03-23 | The Scripps Research Institute | Agonists of stimulator of interferon genes sting |
WO2023284719A1 (en) * | 2021-07-13 | 2023-01-19 | Nanjing University | A pt conjugate and the use thereof |
CA3226976A1 (en) | 2021-07-23 | 2023-01-26 | Immunesensor Therapeutics, Inc. | Sting agonist combination treatments with cytokines |
WO2023103850A1 (zh) * | 2021-12-07 | 2023-06-15 | 中国科学院上海药物研究所 | Sting小分子激动剂、其制备方法及应用 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013508350A (ja) * | 2009-10-20 | 2013-03-07 | ファイザー・インク | ガンマ−セクレターゼモジュレーターとしての新規なヘテロアリールイミダゾールおよびヘテロアリールトリアゾール |
CN103204813A (zh) * | 2012-01-12 | 2013-07-17 | 格兰马克药品股份有限公司 | 作为trpv3拮抗剂的稠合咪唑衍生物 |
ES2692226T3 (es) | 2014-06-04 | 2018-11-30 | Glaxosmithkline Intellectual Property Development Limited | Dinucleótidos cíclicos como moduladores de STING |
MA42608A (fr) | 2015-08-13 | 2018-06-20 | Merck Sharp & Dohme | Composés de di-nucléotide cyclique en tant qu'agonistes sting (stimulateur de gène interféron) |
NZ738202A (en) | 2015-12-03 | 2019-07-26 | Glaxosmithkline Ip Dev Ltd | Cyclic purine dinucleotides as modulators of sting |
US11701364B2 (en) | 2018-02-21 | 2023-07-18 | The Scripps Research Institute | Agonists of stimulator of interferon genes sting |
-
2019
- 2019-02-21 US US15/733,535 patent/US11701364B2/en active Active
- 2019-02-21 EP EP19757913.9A patent/EP3755331A4/en active Pending
- 2019-02-21 CA CA3091670A patent/CA3091670C/en active Active
- 2019-02-21 MX MX2020008771A patent/MX2020008771A/es unknown
- 2019-02-21 WO PCT/US2019/018899 patent/WO2019165032A1/en unknown
- 2019-02-21 JP JP2020544275A patent/JP7104999B2/ja active Active
- 2019-02-21 AU AU2019225919A patent/AU2019225919B2/en active Active
- 2019-02-21 KR KR1020207026762A patent/KR20200123179A/ko not_active Application Discontinuation
- 2019-02-21 CN CN202311816056.XA patent/CN117942342A/zh active Pending
- 2019-02-21 CN CN201980021235.XA patent/CN111971045B/zh active Active
-
2020
- 2020-08-20 IL IL276844A patent/IL276844A/en unknown
-
2022
- 2022-07-04 JP JP2022107875A patent/JP7366456B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
KR20200123179A (ko) | 2020-10-28 |
US11701364B2 (en) | 2023-07-18 |
AU2019225919A1 (en) | 2020-09-24 |
CA3091670C (en) | 2023-02-28 |
EP3755331A4 (en) | 2021-11-17 |
CA3091670A1 (en) | 2019-08-29 |
IL276844A (en) | 2020-10-29 |
CN111971045A (zh) | 2020-11-20 |
AU2019225919B2 (en) | 2022-04-21 |
MX2020008771A (es) | 2020-11-13 |
JP2021514375A (ja) | 2021-06-10 |
JP7104999B2 (ja) | 2022-07-22 |
CN111971045B (zh) | 2024-05-03 |
US20210205321A1 (en) | 2021-07-08 |
JP2022130684A (ja) | 2022-09-06 |
JP7366456B2 (ja) | 2023-10-23 |
EP3755331A1 (en) | 2020-12-30 |
WO2019165032A1 (en) | 2019-08-29 |
RU2020130864A (ru) | 2022-03-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111971045B (zh) | 干扰素基因刺激物sting的激动剂 | |
JP6501948B2 (ja) | ウイルス感染治療のための大環状デアザプリノン | |
CN104781239B (zh) | 用于治疗病毒感染和另外的疾病的烷基嘧啶衍生物 | |
JP2016526550A (ja) | ウイルス感染症および他の疾病の処置のためのピロロ[3,2−d]ピリミジン誘導体 | |
JP2014534231A (ja) | ウイルス感染の治療のためのプリン誘導体 | |
CN115160309A (zh) | Krasg12c突变蛋白杂环类抑制剂的制备及其应用 | |
AU2020332005B2 (en) | Monocyclic agonists of stimulator of interferon genes sting | |
WO2020077944A1 (zh) | 嘌呤系列衍生物及其制备方法和用途 | |
WO2020052489A1 (zh) | 一种6-氨基-1h-吡唑并[3,4-d]嘧啶类jak激酶抑制剂的制备与应用 | |
RU2809022C2 (ru) | Агонисты стимулятора генов интерферона sting | |
WO2015014283A1 (zh) | 蛋白酪氨酸激酶抑制剂及其应用 | |
KR20220066067A (ko) | 인터페론 유전자의 자극인자 sting의 비시클릭 효능제 | |
CN115038701A (zh) | Jak抑制剂的晶型及其应用 | |
CN115490689A (zh) | 不可逆krasg12c抑制剂的制备及其应用 | |
CN108727404B (zh) | 噻吩并[3,2-d]嘧啶类化合物、其制备方法及用途 | |
CN114249753A (zh) | 三唑并吡啶类激酶抑制剂 | |
Tape | The synthesis and optimisation of toll-like receptor agonists as potential immunomodulatory agents | |
JP2024505284A (ja) | イミダゾ[4,5-d]ピリダジンの誘導体、それらの製造およびそれらの治療用途 | |
WO2021147790A1 (zh) | 吡唑并[1,5-a]吡嗪类衍生物及其制备方法和用途 | |
JP2023512204A (ja) | トール様受容体7(TLR7)アゴニストとしての1H-ピラゾロ[4,3-d]ピリミジン化合物 | |
CN114026097A (zh) | 取代的吡唑并喹唑啉酮化合物及其应用 | |
JP2023512207A (ja) | トール様受容体7(TLR7)アゴニストとしての1H-ピラゾロ[4,3-d]ピリミジン化合物 | |
CN111875606A (zh) | 一种基于虚拟对接获得的嘌呤类化合物及其制备方法和应用 | |
CN103748081A (zh) | 用于治疗病毒感染和另外的疾病的喹唑啉衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |