CN111201228B - 作为Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 - Google Patents
作为Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 Download PDFInfo
- Publication number
- CN111201228B CN111201228B CN201880065815.4A CN201880065815A CN111201228B CN 111201228 B CN111201228 B CN 111201228B CN 201880065815 A CN201880065815 A CN 201880065815A CN 111201228 B CN111201228 B CN 111201228B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- formula
- group
- antibody
- 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.)
- Active
Links
- 108010060825 Toll-Like Receptor 7 Proteins 0.000 title claims abstract description 8
- 102000008236 Toll-Like Receptor 7 Human genes 0.000 title claims abstract 3
- 102000002689 Toll-like receptor Human genes 0.000 title abstract description 15
- 108020000411 Toll-like receptor Proteins 0.000 title abstract description 15
- 239000000556 agonist Substances 0.000 title abstract description 12
- RGKBRPAAQSHTED-UHFFFAOYSA-N 8-oxoadenine Chemical class NC1=NC=NC2=C1NC(=O)N2 RGKBRPAAQSHTED-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 125000000217 alkyl group Chemical group 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 39
- -1 cyclic amine Chemical class 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 8
- 210000000987 immune system Anatomy 0.000 abstract description 3
- 210000000056 organ Anatomy 0.000 abstract description 2
- 230000004936 stimulating effect Effects 0.000 abstract description 2
- 239000002671 adjuvant Substances 0.000 abstract 1
- 230000021615 conjugation Effects 0.000 description 38
- 235000001014 amino acid Nutrition 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 28
- 150000001413 amino acids Chemical class 0.000 description 28
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000427 antigen Substances 0.000 description 24
- 108091007433 antigens Proteins 0.000 description 24
- 102000036639 antigens Human genes 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- 206010028980 Neoplasm Diseases 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 20
- 125000005647 linker group Chemical group 0.000 description 19
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- 229920001223 polyethylene glycol Polymers 0.000 description 19
- 125000006850 spacer group Chemical group 0.000 description 19
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000003776 cleavage reaction Methods 0.000 description 13
- 108090000765 processed proteins & peptides Proteins 0.000 description 13
- 230000007017 scission Effects 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 230000006320 pegylation Effects 0.000 description 12
- 102000004196 processed proteins & peptides Human genes 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 102000035195 Peptidases Human genes 0.000 description 9
- 108091005804 Peptidases Proteins 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 125000001931 aliphatic group Chemical group 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 108010010779 glutamine-pyruvate aminotransferase Proteins 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 8
- 101000662009 Homo sapiens UDP-N-acetylglucosamine pyrophosphorylase Proteins 0.000 description 8
- 239000004365 Protease Substances 0.000 description 8
- 102100037921 UDP-N-acetylglucosamine pyrophosphorylase Human genes 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 7
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 7
- 125000001188 haloalkyl group Chemical group 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000003275 alpha amino acid group Chemical group 0.000 description 6
- 235000018417 cysteine Nutrition 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 229940100601 interleukin-6 Drugs 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- ZUHQCDZJPTXVCU-UHFFFAOYSA-N C1#CCCC2=CC=CC=C2C2=CC=CC=C21 Chemical compound C1#CCCC2=CC=CC=C2C2=CC=CC=C21 ZUHQCDZJPTXVCU-UHFFFAOYSA-N 0.000 description 4
- 108090000712 Cathepsin B Proteins 0.000 description 4
- 102000004225 Cathepsin B Human genes 0.000 description 4
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 241001495137 Streptomyces mobaraensis Species 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- ZPWOOKQUDFIEIX-UHFFFAOYSA-N cyclooctyne Chemical compound C1CCCC#CCC1 ZPWOOKQUDFIEIX-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 235000019419 proteases Nutrition 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- PZPNGWWKCSJKOS-UHFFFAOYSA-N 6-fluoropyridine-3-carbaldehyde Chemical compound FC1=CC=C(C=O)C=N1 PZPNGWWKCSJKOS-UHFFFAOYSA-N 0.000 description 3
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 3
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 238000006845 Michael addition reaction Methods 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 102400001018 Proadrenomedullin N-20 terminal peptide Human genes 0.000 description 3
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229960002173 citrulline Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- SHKVHAAEKHGXSM-UHFFFAOYSA-N 2-butoxy-8-methoxy-7h-purin-6-amine Chemical compound CCCCOC1=NC(N)=C2N=C(OC)NC2=N1 SHKVHAAEKHGXSM-UHFFFAOYSA-N 0.000 description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 2
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical group C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 2
- IIVOXPOZSFRJJA-UHFFFAOYSA-N 6-fluoro-2-methylpyridine-3-carbaldehyde Chemical compound CC1=NC(F)=CC=C1C=O IIVOXPOZSFRJJA-UHFFFAOYSA-N 0.000 description 2
- AAQGRPOPTAUUBM-ZLUOBGJFSA-N Ala-Ala-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O AAQGRPOPTAUUBM-ZLUOBGJFSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 102100025221 CD70 antigen Human genes 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 102000003908 Cathepsin D Human genes 0.000 description 2
- 108090000258 Cathepsin D Proteins 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 2
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 2
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 108050006654 Lipocalin Proteins 0.000 description 2
- 102000019298 Lipocalin Human genes 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 102000003735 Mesothelin Human genes 0.000 description 2
- 108090000015 Mesothelin Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 229940124614 TLR 8 agonist Drugs 0.000 description 2
- 102100031293 Thimet oligopeptidase Human genes 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000005237 alkyleneamino group Chemical group 0.000 description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical group O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000013477 citrulline Nutrition 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 150000001945 cysteines Chemical group 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 102000006815 folate receptor Human genes 0.000 description 2
- 108020005243 folate receptor Proteins 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- 230000002998 immunogenetic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 239000002799 interferon inducing agent Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- YKUCHDXIBAQWSF-UHFFFAOYSA-N methyl 3-hydroxybenzoate Chemical compound COC(=O)C1=CC=CC(O)=C1 YKUCHDXIBAQWSF-UHFFFAOYSA-N 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 108010073106 thimet oligopeptidase Proteins 0.000 description 2
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009261 transgenic effect Effects 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
- 108010073969 valyllysine Proteins 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ZXSBHXZKWRIEIA-JTQLQIEISA-N (2s)-3-(4-acetylphenyl)-2-azaniumylpropanoate Chemical compound CC(=O)C1=CC=C(C[C@H](N)C(O)=O)C=C1 ZXSBHXZKWRIEIA-JTQLQIEISA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 125000006724 (C1-C5) alkyl ester group Chemical group 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical group C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 description 1
- VWXIHLCLIOQWRA-UHFFFAOYSA-N 1h-pteridin-2-one Chemical class N1=CC=NC2=NC(O)=NC=C21 VWXIHLCLIOQWRA-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical group C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- KFXDYZXVIHNBFD-UHFFFAOYSA-N 2-(thian-2-ylsulfonyl)thiane Chemical compound C1CCCSC1S(=O)(=O)C1CCCCS1 KFXDYZXVIHNBFD-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical group SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 description 1
- LQILVUYCDHSGEU-UHFFFAOYSA-N 4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1CN1C(=O)C=CC1=O LQILVUYCDHSGEU-UHFFFAOYSA-N 0.000 description 1
- VFOKSTCIRGDTBR-UHFFFAOYSA-N 4-amino-2-butoxy-8-[[3-(pyrrolidin-1-ylmethyl)phenyl]methyl]-5,7-dihydropteridin-6-one Chemical compound C12=NC(OCCCC)=NC(N)=C2NC(=O)CN1CC(C=1)=CC=CC=1CN1CCCC1 VFOKSTCIRGDTBR-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- LTFHNKUKQYVHDX-UHFFFAOYSA-N 4-hydroxy-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1O LTFHNKUKQYVHDX-UHFFFAOYSA-N 0.000 description 1
- SJISCEAZUHNOMD-UHFFFAOYSA-N 4-phenylcyclohexan-1-amine Chemical class C1CC(N)CCC1C1=CC=CC=C1 SJISCEAZUHNOMD-UHFFFAOYSA-N 0.000 description 1
- CGRRUFNHHQCLDZ-UHFFFAOYSA-N 5-hydroxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(O)C=N1 CGRRUFNHHQCLDZ-UHFFFAOYSA-N 0.000 description 1
- UEIOLEMXCBOQAX-UHFFFAOYSA-N 6-amino-2-(butylamino)-9-[(6-methylpyridin-3-yl)methyl]-7h-purin-8-one Chemical compound C12=NC(NCCCC)=NC(N)=C2N=C(O)N1CC1=CC=C(C)N=C1 UEIOLEMXCBOQAX-UHFFFAOYSA-N 0.000 description 1
- HEKGNUXGYUZNHH-UHFFFAOYSA-N 6-amino-9-benzyl-2-butoxy-7h-purin-8-one Chemical compound C12=NC(OCCCC)=NC(N)=C2N=C(O)N1CC1=CC=CC=C1 HEKGNUXGYUZNHH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- ZIBWKCRKNFYTPT-ZKWXMUAHSA-N Ala-Asn-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O ZIBWKCRKNFYTPT-ZKWXMUAHSA-N 0.000 description 1
- LIWMQSWFLXEGMA-WDSKDSINSA-N Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)N LIWMQSWFLXEGMA-WDSKDSINSA-N 0.000 description 1
- 238000012815 AlphaLISA Methods 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- XWKBWZXGNXTDKY-ZKWXMUAHSA-N Asp-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O XWKBWZXGNXTDKY-ZKWXMUAHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 238000007184 Barbier reaction Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CSCBHWONKPLQCM-UHFFFAOYSA-N C(=O)O.OC=1C=NC=CC1 Chemical compound C(=O)O.OC=1C=NC=CC1 CSCBHWONKPLQCM-UHFFFAOYSA-N 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 102100038078 CD276 antigen Human genes 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 240000005589 Calophyllum inophyllum Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000003902 Cathepsin C Human genes 0.000 description 1
- 108090000267 Cathepsin C Proteins 0.000 description 1
- 108090000619 Cathepsin H Proteins 0.000 description 1
- 102000004175 Cathepsin H Human genes 0.000 description 1
- 108090000624 Cathepsin L Proteins 0.000 description 1
- 102000004172 Cathepsin L Human genes 0.000 description 1
- 108090000613 Cathepsin S Proteins 0.000 description 1
- 102100035654 Cathepsin S Human genes 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000053187 Glucuronidase Human genes 0.000 description 1
- 108010060309 Glucuronidase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000010956 Glypican Human genes 0.000 description 1
- 108050001154 Glypican Proteins 0.000 description 1
- 108050007237 Glypican-3 Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101000763579 Homo sapiens Toll-like receptor 1 Proteins 0.000 description 1
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 description 1
- 101710099452 Inactive tyrosine-protein kinase 7 Proteins 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 1
- VWPJQIHBBOJWDN-DCAQKATOSA-N Lys-Val-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O VWPJQIHBBOJWDN-DCAQKATOSA-N 0.000 description 1
- 108010090665 Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000574441 Mus musculus Alkaline phosphatase, germ cell type Proteins 0.000 description 1
- 101100481579 Mus musculus Tlr11 gene Proteins 0.000 description 1
- 101100481580 Mus musculus Tlr12 gene Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 125000004633 N-oxo-pyridyl group Chemical group 0.000 description 1
- KCTZOTUQSGYWLV-UHFFFAOYSA-N N1C=NC=C2N=CC=C21 Chemical compound N1C=NC=C2N=CC=C21 KCTZOTUQSGYWLV-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 1
- 108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102100027010 Toll-like receptor 1 Human genes 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 description 1
- QRZVUAAKNRHEOP-GUBZILKMSA-N Val-Ala-Val Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O QRZVUAAKNRHEOP-GUBZILKMSA-N 0.000 description 1
- XXDVDTMEVBYRPK-XPUUQOCRSA-N Val-Gln Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O XXDVDTMEVBYRPK-XPUUQOCRSA-N 0.000 description 1
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- IOUPEELXVYPCPG-UHFFFAOYSA-N Valylglycine Chemical compound CC(C)C(N)C(=O)NCC(O)=O IOUPEELXVYPCPG-UHFFFAOYSA-N 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=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
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 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
- 150000005347 biaryls Chemical group 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001023 centrifugal evaporation Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical class [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 125000002944 cyanoaryl group Chemical group 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 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
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000022811 deglycosylation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000005509 dibenzothiophenyl group Chemical group 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 102000045715 human TLR7 Human genes 0.000 description 1
- 102000045720 human TLR8 Human genes 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000011488 interferon-alpha production Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-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
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011159 matrix material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229940120152 methyl 3-hydroxybenzoate Drugs 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- YYAYXDDHGPXWTA-UHFFFAOYSA-N methyl 5-hydroxypyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(O)C=N1 YYAYXDDHGPXWTA-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-O methylsulfide anion Chemical compound [SH2+]C LSDPWZHWYPCBBB-UHFFFAOYSA-O 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- DAZSWUUAFHBCGE-KRWDZBQOSA-N n-[(2s)-3-methyl-1-oxo-1-pyrrolidin-1-ylbutan-2-yl]-3-phenylpropanamide Chemical compound N([C@@H](C(C)C)C(=O)N1CCCC1)C(=O)CCC1=CC=CC=C1 DAZSWUUAFHBCGE-KRWDZBQOSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 230000007030 peptide scission Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 150000003212 purines Chemical class 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
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003248 quinolines Chemical class 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
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 229950010550 resiquimod Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VUFNRPJNRFOTGK-UHFFFAOYSA-M sodium;1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 VUFNRPJNRFOTGK-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 238000011830 transgenic mouse model 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
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229950003036 vesatolimod Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- 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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
- A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6839—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses
- A61K47/6841—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses the antibody targeting a RNA virus
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及具有式(I)或式(II)结构的化合物,其中R1、R2、R3、R4、Ar和X1如本文中所定义,所述化合物为Toll样受体7(TLR7)的激动剂,且可用作用于刺激免疫系统的佐剂。一些此类化合物可以缀合物形式使用以靶向递送至预期作用的器官或组织。
Description
相关申请的交叉引用
本申请根据35 U.S.C.§119(e)主张2017年8月16提交的美国临时申请第62/546,222号的权益;该申请的公开内容以引用的方式并入本文中。
技术领域
本发明涉及Toll样受体7(“TLR7”)激动剂及其缀合物,以及此类激动剂及其缀合物的制备和使用方法。
背景技术
Toll样受体(“TLR”)为识别病原体相关分子模式(“PAMP”)的细胞表面受体。TLR通过结合相应PAMP而活化,其用信号发送病原体的可能感染且刺激免疫系统以对抗该感染。人类具有11种TLR,称为TLR1至TLR11。
通过激动剂活化TLR(主要研究TLR7)可通过刺激免疫反应而对疫苗和免疫疗法剂在治疗除真正病原体感染外的各种病状中的作用具有辅助作用。
TLR7识别与单股RNA病毒相关的PAMP。其活化诱导诸如IFNα和IFNβ的I型干扰素分泌(Lund等人2004)。TLR7具有两个结合位点,一个用于诸如ssRNA40的单股RNA配体(等人2007)且一个用于鸟苷(Zhang等人2016)。
TLR7可结合至类鸟苷合成激动剂且由其活化,此类激动剂诸如基于1H-咪唑并[4,5-c]喹啉骨架的咪喹莫特(imiquimod)、雷西莫特(resiquimod)和嘎德莫特(gardiquimod)。
还已知基于喋啶酮分子骨架的合成TLR7激动剂,实例如已处于2期临床试验的威沙立德(vesatolimod)(Desai等人2015)。据报导,威沙立德的效能比相应的嘌呤-8-酮化合物的效能小100倍,如通过IFN-α诱导所测量(Roethle等人2013)。
其他合成TLR7激动剂基于通常根据式(A)的类嘌呤骨架:
其中R、R'和R″为结构变量,其中R″通常含有未经取代或经取代的芳环或杂芳环。
具有类嘌呤的生物活性分子及其用于治疗诸如纤维化、炎性病症、癌症或致病性感染的病状的用途的公开案包括:Akinbobuyi等人2015b和2016;Barberis等人2012;Carson等人2014;Ding等人2016、2017a和2017b;Graupe等人2015;Hashimoto等人2009;Holldack等人2012;Isobe等人2009a和2012;Jin等人2017a和2017b;Peterson 2014;Pryde2010;和Seifert2015。
基团R”可为吡啶基:Bonfanti等人2015a和2015b;Halcomb等人2015;Hirota等人2000;Isobe等人2000、2002、2004、2006、2009a、2011和2012;Kasibhatla等人2007;Koga-Yamakawa等人2013;Musmuca等人2009;Nakamura 2012;Ogita等人2007;和Yu等人2013。
Bonfanti等人2015b公开了TLR7调节剂,其中一个大环跨越嘌呤部分的两个环:
TLR7激动剂可与搭配物分子缀合,该搭配物分子可为例如磷脂、聚(乙二醇)(“PEG”)或另一TLR(通常为TLR2)。例示性公开案包括:Carson等人2013、2015和2016;Chan等人2009和2011;Lioux等人2016;Maj等人2015;Ban等人2017;Vernejoul等人2014;和Zurawski等人2012。还已公开了与抗体的缀合:Akinbobuyi等人2013和2015a,和Gadd等人2015。常见缀合位点位于式(A)的基团R”处。
还已公开基于5H-吡咯并[3,2-d]嘧啶骨架的TLR7激动剂。参见Cortez等人2017a和2017b;McGowan等人2017;和Li等人2018。
Jensen等人2015公开了阳离子脂质媒介物用于递送TLR7激动剂的用途。
一些TLR7激动剂(包括雷西莫特)为双重TLR7/TLR8激动剂。参见例如Beesu等人2017;Lioux等人2016;和Vernejoul等人2014。
还已公开基于5H-吡咯并[3,2-d]嘧啶骨架的TLR7激动剂。参见Cortez等人2017a和2017b;McGowan等人2017;和Li等人2018。
本文所引用的第一作者或发明者的文献的完整引用和年份列于本说明书末尾。
发明内容
在一个方面中,本说明书提供一种具有式(I)或式(II)结构的化合物
其中
R1为(C1-C5烷基)O、(C1-C2烷基)O(CH2)2-3O、(C1-C5烷基)C(=O)O、(C1-C5烷基)NH、(C1-C2烷基)O(CH2)2-3NH或(C1-C5烷基)C(=O)NH;
X在每次出现时独立地为CR2或N;
R2在每次出现时独立地为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN或NO2;
R3为O、S、NH或N(C1-C3烷基);
Ar为
其中Y、Y′和Y″中的一个选自-0-、-S-、-NH-和-N(C1-C3烷基)-,且Y、Y'和Y”中的另外两个选自=N-和=CR2-;
R4为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN、NO2或(CH2)xR5,其中下标x为1、2、3或4;且
R5为卤素、OH、CN、NH2、NH(C1-C5烷基)、N(C1-C5烷基)2、NH(C3-C6环烷基)、NH(C4-C8双环烷基)、NH(C6-C10螺环烷基)、N(C3-C6环烷基)2、NH(CH2)1-3(芳基)、N((CH2)1-3(芳基))2、具有结构的环胺部分、6元芳香族或杂芳香族部分或者5元杂芳香族部分;
其中
烷基、环烷基、双环烷基、螺环烷基、环胺、6元芳香族或杂芳香族部分或者5元杂芳香族部分任选地经一或多个选自以下的取代基取代:OH、卤素、CN、(C1-C3烷基)、O(C1-C3烷基)、C(=O)(C1-C3烷基)、SO2(C1-C3烷基)、CO2(C1-C3烷基)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2和N(C1-C3烷基)2;且
环烷基、双环烷基、螺环烷基或环胺部分可具有经O、S、NH、N(C1-C3烷基)或N(Boc)替换的CH2基团。
式(I)和式(II)化合物具有作为TLR7激动剂的活性,且其中一些可经缀合以靶向递送至预期作用的靶组织或器官。
附图说明
图1、图2、图3和图7示出用于制备本发明化合物的方案。
图4和图5示出用于连接接头与本发明化合物以使得所述化合物适合于缀合的方案。
图6为示出本发明化合物的TLR7激动作用活性的代表性图。
具体实施方式
定义
“抗体”意指完整抗体及其任何抗原结合片段(即“抗原结合部分”)或单链变体。完整抗体为包含由二硫键相互连接的至少两条重(H)链和两条轻(L)链的蛋白。各重链包含重链可变区(VH)及包含三个域CH1、CH2和CH3的重链恒定区。各轻链包含轻链可变区(VL或Vk)及包含单一域CL的轻链恒定区。VH和VL区可进一步再分成高变区,称为互补决定区(CDR),穿插有较保守框架区(FR)。各VH和VL包含三个CDR和四个FR,其自氨基至羧基端以如下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。可变区含有与抗原相互作用的结合域。恒定区可介导抗体与宿主组织或因子的结合,包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分(Clq)。抗体在抗体以5×10-8M或更小、更优选1×10-8M或更小、更优选6×10-9M或更小、更优选3×10-9M或更小、甚至更优选2×10-9M或更小的KD结合于抗原X时称为“特异性结合”于抗原X。抗体可为嵌合抗体、人源化抗体或优选人类抗体。重链恒定区可经工程化改造以影响糖基化类型或程度,延长抗体半衰期,增强或减少与效应细胞或补体系统的相互作用,或调节一些其他性质。工程化改造可通过替换、添加或删除一或多个氨基酸或通过用来自另一免疫球蛋白类型的域替换域或前述方法的组合来完成。
抗体的“抗原结合片段”和“抗原结合部分”(或简单地“抗体部分”或“抗体片段”)意指抗体的保留特异性结合于抗原的能力的一或多个片段。已证实抗体的抗原结合功能可通过全长抗体的片段执行,此类片段诸如(i)Fab片段,其为由VL、VH、CL和CH1域构成的单价片段;(ii)F(ab')2片段,其为包含由铰链区处的二硫桥连接的两个Fab片段的二价片段;(iii)Fab'片段,其基本上为具有铰链区部分的Fab(参见例如Abbas等人,Cellular andMolecular Immunology,第6版,Saunders Elsevier 2007);(iv)Fd片段,其由VH和CH1域组成;(v)Fv片段,其由抗体的单臂的VL和VH域组成;(vi)dAb片段(Ward等人,(1989)Nature341:544-546),其由VH域组成;(vii)经分离的互补决定区(CDR);和(viii)纳米抗体,其为含有单一可变域和两个恒定域的重链可变区。优选的抗原结合片段为Fab、F(ab')2、Fab'、Fv和Fd片段。此外,尽管Fv片段的两个域VL和VH由单独的基因编码,但该域可使用重组方法通过合成接头接合,该合成接头使得该域能够形成为其中VL区与VH区配对形成单价分子的单一蛋白链(称为单链Fv或scFv);参见例如Bird等人(1988)Science242:423-426;和Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。此类单链抗体也涵盖于术语抗体的“抗原结合部分”内。
除非另外规定,否则根据Kabat系统(Kabat等人,“Sequences of proteins ofimmunological interest”,第5版,公开案第91-3242号,美国卫生与公众服务部(U.S.Dept.Health&Human Services),NIH,Bethesda,Md.,1991,以下简称“Kabat”)提及抗体重链或轻链可变区(VH或VL)中氨基酸位置的编号(例如提及SEQ ID NO:清单中的直链编号),且根据如Kabat中所列的EU索引提及抗体重链或轻链恒定区(CH1、CH2、CH3或CL)中氨基酸位置的编号。参见Lazar等人的US 2008/0248028A1,该文献的例如此类使用的公开内容以引用的方式并入本文中。此外,免疫遗传学信息系统(ImMunoGeneTics InformationSystem;IMGT)在其网站提供了名称为“IMGT Scientific Chart:Correspondence betweenC Numberings”的表,其展示其用于重链恒定区的编号系统、EU编号和Kabat编号之间的对应关系。
“经分离抗体”意指基本上不含具有不同抗原特异性的其他抗体的抗体(例如特异性结合抗原X的经分离抗体基本上不含特异性结合除抗原X以外的抗原的抗体)。然而,特异性结合抗原X的经分离抗体可与诸如来自其他物种的抗原X分子的其他抗原具有交叉反应性。在某些实施方案中,经分离抗体特异性结合于人类抗原X且不与其他(非人类)抗原X抗原交叉反应。此外,经分离抗体可基本上不含其他细胞物质和/或化学物质。
“单克隆抗体”或“单克隆抗体组合物”意指具有单一分子组成的抗体分子的制剂,其对特定抗原表位展现单一结合特异性和亲和力。
“人类抗体”意指具有如下可变区的抗体,其中框架区与CDR区(和恒定区(若存在))均衍生自人类生殖系免疫球蛋白序列。人类抗体可包括后续修饰,包括天然或合成修饰。人类抗体可包括并非由人类生殖系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或定点突变诱发或通过体内体细胞突变引入的突变)。然而,“人类抗体”不包括源自另一哺乳动物物种(诸如小鼠)的生殖系的CDR序列已经移植至人类框架序列上的抗体。
“人类单克隆抗体”意指呈现单一结合特异性的抗体,其具有如下可变区,其中框架区与CDR区均衍生自人类生殖系免疫球蛋白序列。在一个实施方案中,人类单克隆抗体由融合瘤产生,该融合瘤包括与永生化细胞融合的获自转基因非人类动物(例如转基因小鼠)的B细胞,该转基因非人类动物具有包含人类重链转基因和轻链转基因的基因组。
“脂族基”意指直链或支链、饱和或不饱和的非芳香族烃部分,其具有指定数目个碳原子(例如,如在“C3脂族基”、“C1-5脂族基”、“C1-C5脂族基”或“C1至C5脂族基”中,后面三个词组为具有1至5个碳原子的脂族部分的同义词),或在未明确指定碳原子数目时具有1至4个碳原子(在不饱和脂族部分的实例中具有2至4个碳原子)。类似理解适用于其他类型中的碳数目,如在C2-4烯烃、C4-C7环脂族基等中。以类似方式,诸如“(CH2)1-3”的术语应理解为下标为1、2或3的简写,因而此类术语表示CH2、CH2CH2和CH2CH2CH2。
“烷基”意指饱和脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C1-C4烷基部分包括(但不限于)甲基、乙基、丙基、异丙基、异丁基、叔丁基、1-丁基、2-丁基等。“亚烷基”意指烷基的二价对应物,诸如CH2CH2、CH2CH2CH2和CH2CH2CH2CH2。
“烯基”意指具有至少一个碳-碳双键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4烯基部分包括(但不限于)乙烯基(ethenyl/vinyl)、2-丙烯基(烯丙基或丙-2-烯基)、顺-1-丙烯基、反-1-丙烯基、E-(或Z-)2-丁烯基、3-丁烯基、1,3-丁二烯基(丁-1,3-二烯基)等。
“炔基”意指具有至少一个碳-碳三键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4炔基包括乙炔基(ethynyl/acetylenyl)、炔丙基(丙-2-炔基)、1-丙炔基、丁-2-炔基等。
“环脂族基”意指具有1至3个环的饱和或不饱和、非芳香族烃部分,各环具有3至8个(优选3至6个)碳原子。“环烷基”意指其中各环饱和的环脂族部分。“环烯基”意指其中至少一个环具有至少一个碳-碳双键的环脂族部分。“环炔基”意指其中至少一个环具有至少一个碳-碳三键的环脂族部分。以说明的方式,环脂族部分包括(但不限于)环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基和金刚烷基。优选的环脂族部分为环烷基部分,尤其环丙基、环丁基、环戊基和环己基。“亚环烷基”意指环烷基的二价对应物。
“杂环脂族基”意指如下环脂族部分,其中在其至少一个环中,至多三个(优选1至2个)碳经独立地选自N、O或S的杂原子替换,其中N和S可任选地经氧化且N可任选地经季铵化。优选的环脂族部分由大小为5元至6元的一个环组成。类似地,“杂环烷基”、“杂环烯基”和“杂环炔基”分别意指环烷基、环烯基或环炔基部分,其中其至少一个环经如此修饰。例示性杂环脂族部分包括氮杂环丙烷基、氮杂环丁烷基、1,3-二氧杂环己烷基、氧杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、四氢吡喃基、四氢噻喃基、四氢噻喃基砜、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1,3-二氧戊环基、四氢-1,1-二氧代噻吩基、1,4-二氧杂环己烷基、硫杂环丁烷基等。“亚杂环烷基”意指杂环烷基的二价对应物。
“烷氧基”、“芳基氧基”、“烷基硫基”和“芳基硫基”分别意指-O(烷基)、-O(芳基)、-S(烷基)和-S(芳基)。实例分别为甲氧基、苯氧基、甲基硫基和苯基硫基。
除非指示较窄含义,否则“卤素”或“卤代”意指氟、氯、溴或碘。
“芳基”意指具有单环、双环或三环环系统(优选单环)的烃部分,其中各环具有3至7个碳原子且至少一个环为芳香族。环系统中的环可彼此稠合(如在萘基中)或彼此键合(如在联苯中)且可与非芳香族环稠合或键合(如在茚满基或环己基苯基中)。以进一步说明的方式,芳基部分包括(但不限于)苯基、萘基、四氢萘基、茚满基、联苯、菲基、蒽基和苊基。“亚芳基”意指芳基的二价对应物,例如1,2-亚苯基、1,3-亚苯基或1,4-亚苯基。
“杂芳基”意指具有单环、双环或三环环系统(优选5元至7元单环)的部分,其中各环具有3至7个碳原子,且至少一个环为含有1至4个独立地选自N、O或S的杂原子的芳环,其中N和S可任选地经氧化且N可任选地经季铵化。此类至少一个含杂原子芳环可与其他类型的环稠合(如在苯并呋喃基或四氢异喹啉基中)或与其他类型的环直接键合(如在苯基吡啶基或2-环戊基吡啶基中)。以进一步说明的方式,杂芳基部分包括吡咯基、呋喃基、噻吩基(thiophenyl或thienyl)、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、四唑基、吡啶基、N-氧代吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基、喹唑啉基(quinazolinyl)、噌啉基、喹喔啉基(quinozalinyl)、二氮杂萘基、苯并呋喃基、吲哚基、苯并噻吩基、噁二唑基、噻二唑基、苯并噻唑基、苯并咪唑基、苯并三唑基、二苯并呋喃基、咔唑基、二苯并噻吩基、吖啶基等。“亚杂芳基”意指杂芳基的二价对应物。
若据指示部分可经取代,诸如如在“未经取代或经取代的C1-C5烷基”或“任选地经取代的杂芳基”中通过使用“未经取代或经取代”或“任选地经取代”措辞,则此类部分可具有一或多个独立选择的取代基,优选数目为一至五个,更优选数目为一个或两个。取代基和取代模式可由本领域普通技术人员考虑取代基所连接的部分而选择,以提供化学上稳定且可通过本领域中已知的技术以及本文所阐述的方法合成的化合物。若一个部分鉴别为“未经取代或经取代”或“任选地经取代”,则在一优选实施方案中,此类部分未经取代。
“芳基烷基”、“(杂环脂族基)烷基”、“芳基烯基”、“芳基炔基”、“联芳基烷基”等意指烷基、烯基或炔基部分,任选地可经芳基、杂环脂族基、联芳基等部分取代,任选地可在烷基、烯基或炔基部分上具有开放(不饱和)价态,例如如在苯甲基、苯乙基、N-咪唑基乙基、N-吗啉基乙基等中。相反地,“烷基芳基”、“烯基环烷基”等意指芳基、环烷基等部分,任选地可经烷基、烯基等部分取代,任选地可例如如在甲基苯基(甲苯基)或烯丙基环己基中。“羟基烷基”、“卤代烷基”、“烷基芳基”、“氰基芳基”等意指烷基、芳基等部分,任选地可经一或多个所鉴别取代基(视情况可为羟基、卤素等)取代。
举例而言,可容许的取代基包括(但不限于)烷基(尤其甲基或乙基)、烯基(尤其烯丙基)、炔基、芳基、杂芳基、环脂族基、杂环脂族基、卤素(尤其氟)、卤代烷基(尤其三氟甲基)、羟基、羟基烷基(尤其羟基乙基)、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)(尤其-OCF3)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)、-SO2N(烷基)2等。
若经取代的部分为脂族部分,则优选的取代基为芳基、杂芳基、环脂族基、杂环脂族基、卤素、羟基、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(=O)烷基、-S(环烷基)、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)和-SO2N(烷基)2。更优选的取代基为卤素、羟基、氰基、硝基、烷氧基、-O(芳基)、=O、=NOH、=NO(烷基)、-OC(=O)(烷基)、-OC(=O)O(烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2和-NHC(=NH)NH2。尤其优选的为苯基、氰基、卤素、羟基、硝基、C1-C4烷氧基、O(C2-C4亚烷基)OH和O(C2-C4亚烷基)卤素。
若经取代的部分为环脂族、杂环脂族、芳基或杂芳基部分,则优选的取代基为烷基、烯基、炔基、卤素、卤代烷基、羟基、羟基烷基、氰基、硝基、烷氧基、-O(羟基烷基)、-O(卤代烷基)、-O(芳基)、-O(环烷基)、-O(杂环烷基)、烷基硫基、芳基硫基、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟基烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)和-SO2N(烷基)2。更优选的取代基为烷基、烯基、卤素、卤代烷基、羟基、羟基烷基、氰基、硝基、烷氧基、-O(羟基烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟基烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟基烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟基烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2和-NHC(=NH)NH2。尤其优选的为C1-C4烷基、氰基、硝基、卤素和C1-C4烷氧基。
若陈述一范围,如同“C1-C5烷基”或“5至10%”,则此类范围包括范围的端点,如同第一实例中的C1和C5及第二实例中的5%和10%。
除非特别指示特定立体异构体(例如通过结构式中相关立构中心的加粗或短划键,通过将结构式中的双键描述为具有E或Z构型或通过使用指明立体化学的命名法),否则所有立体异构体均以纯化合物以及其混合物的形式包括在本发明的范围内。除非另外指明,否则个别对映异构体、非对映异构体、几何异构体及其组合及混合物均由本发明涵盖。
本领域技术人员将了解,化合物可具有互变异构形式(例如酮和烯醇形式)、共振形式和两性离子形式,其等效于本文所用的结构式中所描绘的形式,且该结构式涵盖此类互变异构、共振或两性离子形式。
“药学上可接受的酯”意指体内(例如在人体中)水解产生母体化合物或其盐或自身活性类似于母体化合物的酯。适合的酯包括C1-C5烷基酯、C2-C5烯基酯或C2-C5炔基酯,尤其甲酯、乙酯或正丙酯。
“药学上可接受的盐”意指适用于药物制剂的化合物的盐。若化合物具有一或多个碱性基团,则盐可为酸加成盐,诸如硫酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、马来酸盐、柠檬酸盐、磷酸盐、乙酸盐、双羟萘酸盐(恩波酸盐(embonate))、氢碘酸盐、硝酸盐、盐酸盐、乳酸盐、甲基硫酸盐、富马酸盐、苯甲酸盐、琥珀酸盐、甲磺酸盐、乳糖酸盐、辛二酸盐、甲苯磺酸盐等。若化合物具有一或多个酸性基团,则盐可为如下盐,诸如钙盐、钾盐、镁盐、葡甲胺盐、铵盐、锌盐、哌嗪盐、氨丁三醇盐、锂盐、胆碱盐、二乙胺盐、4-苯基环己胺盐、苄星青霉素(benzathine)盐、钠盐、四甲铵盐等。多晶型结晶形式和溶剂合物也涵盖在本发明的范围内。
在本说明书的式中,穿过键的波浪线或键末尾的星号(*)表示共价连接位点。举例而言,对式中R为或R为的陈述意指
在本说明书的该式中,穿过芳环在其两个碳之间的键意指连接至该键的基团可位于该芳环中通过移除隐含存在的氢而变得可用的任何位置处。以说明的方式,式表示在另一说明中,表示
一般而言,出于一致性和便利性,在本文中以烯醇形式呈现互变异构结构。
本领域技术人员将了解,该互变异构结构还可以等效酮形式呈现,且两种互变异构体等效。
化合物
式(I)和式(II)中的R1优选为n-BuO、n-BuNH、EtO、MeO或MeOCH2CH2O;更优选为n-BuO或MeOCH2CH2O;且最优选为n-BuO。
在式(I)和式(II)中,各R2优选为H。
在式(I)和式(II)中,R3优选为O。
在一个实施方案中,式(I)化合物由式(I′)表示,其中各X′独立地为CH或N,且R1、Ar和R4如上文关于式(I)/(II)所定义:
在一个实施方案中,式(II)化合物由式(II′)表示,其中各X′独立地为CH或N,且R1、Ar和R4如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Ia)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Ib)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Ic)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Id)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Ie)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(If)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(I)化合物由式(Ig)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在一个实施方案中,式(II)化合物由式(IIa)表示,其中x、R1和R5如上文关于式(I)/(II)所定义:
在式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)、式(If)和式(IIa)中,优选地,R1为n-BuO且下标x为1。
在式(I)、式(I′)、式(II)、式(II′)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)、式(If)和式(IIa)(在前四个式中,在R4为(CH2)xR5的个例中x优选为1)中,R5优选为OH、Cl、
优选地,在式(I)和式(II)中,任何给定芳香环中不超过两个X且更优选不超过一个X为N。
优选地,在式(I')、式(II')、式(Ia)、式(Ib)、式(IIa)和式(IId)中,任何给定芳香环中不超过两个X且更优选不超过一个X为N。
式(Ia)化合物的实例包括:
式(Ib)化合物的实例包括:
式(Ic)化合物的实例包括:
式(Id)化合物的实例包括:
式(Ie)化合物的实例包括:
式(If)化合物的实例包括:
式(Ig)化合物的实例为:
式(IIa)化合物的实例包括:
表A呈现本文中所公开的化合物的生物活性数据。一组数据涉及使用HEK-BlueTMTLR7报导测定的TLR7激动作用活性,如下文中所描述。另一组数据涉及白介素6(IL-6)的诱导,白介素6是在TLR7途径中起重要作用的细胞介素。出于比较,也呈现雷西莫特、威沙立德、嘎德莫特和化合物B(CAS登记号226906-84-9)的活性。
缀合物
综述
本文中所公开的TLR7激动剂可通过局部给药或通过以与靶向部分的缀合物形式靶向递送而递送至预期作用位点。优选地,靶向部分为抗体或其抗原结合部分,且其抗原位于预期作用位置,例如若预期作用位点位于肿瘤(癌症)则其抗原为肿瘤相关抗原。优选地,相比于正常细胞,癌细胞唯一表现或过度表现肿瘤相关抗原。肿瘤相关抗原可位于癌细胞表面上或由癌细胞分泌至其环境中。
在一个方面中,提供一种包含本发明化合物和配体的缀合物,其由式(IV)表示
[D(XD)a(C)c(XZ)b]mZ (IV)
其中Z为靶向部分,D为本发明的激动剂,且-(XD)aC(XZ)b-由于它们连接Z与D而统称为“连接部分”或“接头”。在接头内,C为经设计以在D的预期生物学作用位点处或附近裂解的可裂解基团;XD和XZ分别为间隔开D与C及C与Z之间隔部分(或“间隔基”);下标a、b和c独立地为0或1(即,XD、XZ和C任选地存在)。下标m为1、2、3、4、5、6、7、8、9或10(优选1、2、3或4)。D、XD、C、XZ和Z更充分描述于下文中。
通过结合于安置有其抗原或受体的靶组织或细胞,Z将缀合物引导至此处。基团C在标靶组织或细胞处的裂解释放D,从而局部地发挥其效应。以此方式,达成D在预期作用位点的精确递送,从而降低所需剂量。另外,D在处于其缀合状态时通常没有生物活性(或活性明显更低),从而减少脱靶效应。
如由下标m所反映,取决于可供用于缀合的位点Z的数目和所用实验条件,各Z可与多于一个D缀合。本领域技术人员将了解,虽然各个别Z与整数数目个D至和,但是缀合物的制备可分析D与Z的非整数比率,其反映统计平均值。此比率称为取代比率(“SR”)或药物-抗体比率(“DAR”)。
靶向部分Z
优选地,靶向部分Z为抗体。为方便和简洁起见且以非限制方式,本说明书中关于Z及其缀合物的详细论述以其为抗体的情形书写,但本领域技术人员将理解,其他类型的Z也可在细节上作必要修改后缀合。举例而言,带有作为靶向部分的叶酸的缀合物可靶向表面上具有叶酸受体的靶细胞(Leamon等人,Cancer Res.2008,68(23),9839)。出于相同原因,本说明书中的详细论述主要关于1:1比率的Z与D(m=1)书写。
可用于本发明缀合物中的抗体包括识别以下抗原的抗体:间皮素、前列腺特异性膜抗原(PSMA)、CD19、CD22、CD30、CD70、B7H3、B7H4(也称为O8E)、蛋白酪氨酸激酶7(PTK7)、磷脂酰肌醇蛋白聚糖-3、RG1、岩藻糖基-GM1、CTLA-4和CD44。抗体可为动物(例如鼠类)抗体、嵌合抗体、人源化抗体或优选人类抗体。抗体优选为单克隆抗体,尤其单克隆人类抗体。针对前述抗原中的一些的人类单克隆抗体的制备公开于以下文献中:Korman等人,US 8,609,816B2(2013;B7H4,也称为08E;具体为抗体2A7、1G11和2F9);Rao-Naik等人,8,097,703B2(2012;CD19;具体为抗体5G7、13F1、46E8、21D4、21D4a、47G4、27F3和3C10);King等人,US 8,481,683B2(2013;CD22;具体为抗体12C5、19A3、16F7和23C6);Keler等人,US7,387,776B2(2008;CD30;具体为抗体5F11、2H9和17G1);Terrett等人,US8,124,738B2(2012;CD70;具体为抗体2H5、10B4、8B5、18E7和69A7);Korman等人,US 6,984,720B1(2006;CTLA-4;具体为抗体10D1、4B6和1E2);Korman等人,US 8,008,449B2(2011;PD-1;具体为抗体17D8、2D3、4H1、5C4、4A11、7D3和5F4);Huang等人,US 2009/0297438A1(2009;PSMA;具体为抗体1C3、2A10、2F5、2C6);Cardarelli等人,US 7,875,278B2(2011;PSMA;具体为抗体4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5和1C3);Terrett等人,US 8,222,375B2(2012;PTK7;具体为抗体3G8、4D5、12C6、12C6a和7C8);Harkins等人,US 7,335,748B2(2008;RG1;具体为抗体A、B、C和D);Terrett等人,US 8,268,970B2(2012;间皮素;具体为抗体3C10、6A4和7B1);Xu等人,US 2010/0092484A1(2010;CD44;具体为抗体14G9.B8.B4、2D1.A3.D12和1A9.A6.B9);Deshpande等人,US8,258,266B2(2012;IP10;具体为抗体1D4、1E1、2G1、3C4、6A5、6A8、7C10、8F6、10A12、10A12S和13C4);Kuhne等人,US 8,450,464B2(2013;CXCR4;具体为抗体F7、F9、D1和E2);和Korman等人,US 7,943,743B2(2011;PD-L1;具体为抗体3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7和13G4);这些文献的公开内容以引用的方式并入本文中。优选地,抗体为抗间皮素抗体。
除为抗体外,Z还可为抗体片段(诸如Fab、Fab'、F(ab')2、Fd或Fv)或抗体模拟物,诸如亲和抗体(affibody)、单域抗体(dAb)、纳米抗体、单抗体、DARPin、抗运载蛋白(anticalin)、万能抗体(versabody)、双运载蛋白(duocalin)、脂质运载蛋白(lipocalin)或高亲和性多聚体(avimer)。
Z上若干不同反应性基团中的任一个可为缀合位点,包括赖氨酸残基中的ε-氨基、侧链碳水化合物部分、天冬氨酸或谷氨酸侧链上的羧酸基、半胱氨酸-半胱氨酸二硫基和半胱氨酸硫醇基。适用于缀合的抗体反应性基团的综述参见例如Garnett,Adv.DrugDelivery Rev.2001,53,171-216及Dubowchik和Walker,Pharmacology&Therapeutics1999,83,67-123,其公开内容以引用的方式并入本文中。
大部分抗体具有多个赖氨酸残基,其可经由其ε-氨基通过酰胺、脲、硫脲或氨基甲酸酯键而缀合。
可通过若干方法使用半胱氨酸侧链中的硫醇(-SH)基来形成缀合物。该硫醇基可用于在其与接头上的硫醇基之间形成二硫键。另一方法经由与接头上的马来酰亚胺基的迈克尔加成反应(Michael addition)。
通常,尽管抗体具有半胱氨酸残基,但其没有游离的硫醇基,因为其所有半胱氨酸都形成了链内或链间二硫键。为了产生游离的硫醇基,可减少天然二硫基。参见例如Packard等人,Biochemistry 1986,25,3548;King等人,Cancer Res.1994,54,6176;和Doronina等人,Nature Biotechnol.2003,21,778。可替代地,可通过使抗体突变、用半胱氨酸取代另一氨基酸或将半胱氨酸插入多肽链中而引入具有游离-SH基团的半胱氨酸。参见例如Eigenbrot等人,US 7,521,541B2(2009);Chilkoti等人,Bioconjugate Chem.1994,5,504;Urnovitz等人,US 4,698,420(1987);Stimmel等人,J.Biol.Chem.2000,275,30445;Bam等人,US 7,311,902B2(2007);Kuan等人,J.Biol.Chem.1994,269,7610;Poon等人,J.Biol.Chem.1995,270,8571;Junutula等人,Nature Biotechnology 2008,26,925;和Rajpal等人2015年12月21日提交的美国临时申请第62/270245号。在另一方法中,将半胱氨酸添加至重链或轻链的C端。参见例如Liu等人,US 8,865,875B2(2014);Cumber等人,J.Immunol.1992,149,120;King等人,Cancer Res.1994,54,6176;Li等人,BioconjugateChem.2002,13,985;Yang等人,Protein Engineering 2003,16,761;和Olafson等人,Protein Engineering Design&Selection 2004,17,21。本段落中引用的文献的公开内容以引用的方式并入本文中。
接头及其组分
如上文所提及,接头包含多达三个要素:可裂解基团C和任选地存在的间隔基XZ和XD。
基团C在生理条件下可裂解。优选地,基团C在缀合物处于血液循环中时相对稳定,但在缀合物到达其预期作用位点后容易裂解。
优选的基团C为肽,其由靶细胞内的蛋白酶选择性裂解,而不是由血清中的蛋白酶裂解。通常,肽包含1至20个氨基酸,优选1至6个氨基酸,更优选2至3个氨基酸。氨基酸可为天然和/或非天然α-氨基酸。天然氨基酸为由遗传密码编码的氨基酸以及自其衍生的氨基酸,例如羟基脯氨酸、γ-羧基谷氨酸、瓜氨酸和O-磷酸丝氨酸。在本说明书中,术语“氨基酸”还包括氨基酸类似物和模拟物。类似物为如下化合物,其具有天然氨基酸的相同通用H2N(R)CHCO2H结构,但R基团不为天然氨基酸中存在的基团。类似物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜和甲硫氨酸甲基锍。氨基酸模拟物为如下化合物,其具有不同于α-氨基酸的通用化学结构的结构,但以类似于α-氨基酸的方式起作用。氨基酸可具有遗传编码氨基酸的“L”立体化学以及对映异构“D”立体化学。
优选地,C含有为蛋白酶的裂解识别序列的氨基酸序列。许多裂解识别序列为本领域中已知的。参见例如Matayoshi等人Science 247:954(1990);Dunn等人Meth.Enzymol.241:254(1994);Seidah等人Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等人Meth.Enzymol.244:595(1994);Smith等人Meth.Enzymol.244:412(1994);和Bouvier等人Meth.Enzymol.248:614(1995);其公开内容以引用的方式并入本文中。
基团C可经选择以使得其由癌症附近的细胞外基质中所存在的蛋白酶裂解,该蛋白酶例如附近垂死癌细胞所释放的蛋白酶或癌细胞所分泌的肿瘤相关蛋白酶。例示性细胞外肿瘤相关蛋白酶为纤维蛋白溶酶、基质金属蛋白酶(MMP)、Thimet寡肽酶(TOP)和CD10。参见例如Trouet等人,US 7,402,556B2(2008);Dubois等人,US 7,425,541B2(2008);和Bebbington等人,US6,897,034B2(2005)。通常为存在于细胞内部的溶酶体酶的组织蛋白酶D有时存在于肿瘤环境中,有可能由垂死癌细胞所释放。
对于经设计以通过酶裂解的缀合物而言,C优选包含经选择以通过诸如组织蛋白酶B、C、D、H、L和S(尤其组织蛋白酶B)的蛋白酶裂解的氨基酸序列。例示性组织蛋白酶B可裂解肽包括Val-Ala、Val-Cit、Val-Lys、Lys-Val-Ala、Asp-Val-Ala、Val-Ala、Lys-Val-Cit、Ala-Val-Cit、Val-Gly、Val-Gln和Asp-Val-Cit。(在本文中,除非上下文明确指示,否则氨基酸序列以N至C方向书写,如同H2N-AA2-AA1-CO2H。)参见Dubowchik等人,Biorg.Med.Chem.Lett.1998,8,3341;Dubowchik等人,Bioorg.Med.Chem.Lett.1998,8,3347;和Dubowchik等人,Bioconjugate Chem.2002,13,855;其公开内容以引用的方式并入。
可用于裂解肽基接头的另一酶为豆荚蛋白,一种优选在Ala-Ala-Asn处裂解的溶酶体半胱氨酸蛋白酶。
在一个实施方案中,基团C为包含两个氨基酸序列-AA2-AA1-的肽,其中AA1为赖氨酸、精氨酸或瓜氨酸,且AA2为苯丙氨酸、缬氨酸、丙氨酸、亮氨酸或异亮氨酸。在另一实施方案中,C由具有一至三个氨基酸的序列构成,其选自由以下组成的群:Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Lys、Cit、Ser和Glu。更优选地,C为前述群中的两个至三个氨基酸肽。
由单个氨基酸构成的可裂解基团C的制备和设计公开于Chen等人,US8,664,407B2(2014)中,其公开内容以引用的方式并入本文中。
基团C可直接键合于Z或D;即,间隔基XZ或XD任选地可不存在。
在存在时,间隔基XZ提供C与Z之间的空间分隔,以免前者空间干扰后者的抗原结合或后者空间干扰前者的裂解。此外,间隔基XZ可用于赋予缀合物增加的溶解性或降低的凝集性质。间隔基XZ可包含一或多个模块区段,其可组装于任何数目的组合中。间隔基XZ的适合区段的实例为:
及其组合,其中下标g为0或1,且下标h为1至24,优选2至4。这些区段可组合,诸如如下所说明:
若存在,间隔基X。提供C与D之间的空间分隔,以免后者空间上或电子学上干扰前者的裂解。间隔基XD还可用于将其他分子质量和化学官能团引入缀合物中。一般而言,其他质量和官能团将影响缀合物的血清半衰期及其他性质。因此,经由明智选择间隔基,可调节缀合物的血清半衰期。间隔基XD还可类似于上文关于间隔基XZ的描述由模块区段组装。
间隔基XZ和/或XD在存在时优选在Z与C或D与C之间分别提供4至25个原子、更优选4至20个原子的线性分隔。
除共价连接抗体与药物以外,接头可执行其他功能。举例而言,接头可含有聚(乙二醇)(“PEG”)基团。由于缀合步骤通常涉及在水性介质中将药物-接头偶联至抗体,因此PEG基团可增加药物-接头的水溶解度。另外,PEG基团可增加所得ADC的溶解度或降低其凝集。若存在PEG基团,则可将其并入间隔基XZ或XD或两者中。PEG基团中重复单元的数目可为2至20,优选4至10。
间隔基XZ或XD或两者可包含自分解部分。自分解部分为如下部分,其(1)键合至C以及Z或D中的一个,且(2)具有使得自基团C的裂解启动反应序次的结构,从而使自分解部分自身视情况与Z或D脱离。换言之,远离Z或D的位点处的反应(自基团C的裂解)使得XZ-Z或XD-D键也断裂。自分解部分的存在在间隔基XD的情形下为适宜的,因为若在缀合物裂解后间隔基XD或其一部分保持连接于D,则D的生物活性可能受损。在可裂解基团C为多肽的情形下使用自分解部分为尤其适宜的,在该实例中自分解部分通常邻近于该多肽定位,以便防止D在空间上或在电子学上干扰肽裂解。
键合至D的羟基或氨基的例示性自分解部分(i)至(v)如下所示:
自分解部分为虚线a与b(或虚线b与。)之间的结构,其中展示相邻结构特征以提供背景。自分解部分(i)和(v)键合至D-NH2(即经由氨基缀合),而自分解部分(ii)、(iii)和(iv)键合至D-OH(即经由羟基或羧基缀合)。虚线b处的键由于酶(在结构(i)至(v)的实例中为肽酶且在结构(vi)的实例中为β-葡糖醛酸酶)而发生的裂解启动自分解反应序次,其引起虚线a处的键裂解和视情况D-OH或D-NH2的随后释放。以说明的方式,结构(i)和(iv)的自分解机制如下所示:
换言之,自分解基团的一个部分处的第一化学键的裂解启动一连串步骤,其引起自分解基团的另一部分处的第二化学键(将自分解基团连接至药物的化学键)裂解,从而释放药物。
在一些情况下,自分解基团可串联使用,如结构(vii)所示。在此情况下,虚线c处的裂解触发虚线b与c之间的部分通过1,6-消除反应而自我分解,接着虚线a与b之间的部分通过环化-消除反应而自我分解。关于自分解部分的其他公开案参见Carl等人,J.Med.Chem.1981,24,479;Carl等人,WO 81/01145(1981);Dubowchik等人,Pharmacology&Therapeutics 1999,83,67;Firestone等人,US 6,214,345 B1(2001);Toki等人,J.Org.Chem.2002,67,1866;Doronina等人,Nature Biotechnology 2003,21,778(勘误表第941页);Boyd等人,US 7,691,962 B2;Boyd等人,US 2008/0279868A1;Sufi等人,WO2008/083312A2;Feng,US 7,375,078 B2;Jeffrey等人,US 8,039,273;和Senter等人,US2003/0096743 A1;其公开内容以引用的方式并入。
在另一实施方案中,Z与D通过不可裂解接头连接,即不存在C。D的代谢最终将接头减小成不会干扰D的生物活性的较小附接部分。
缀合技术
本文中所公开的TLR7激动剂的缀合物优选通过以下方式制得:首先制备包含D和接头(XD)a(C)c(XZ)b(其中XD、C、XZ、a、b和c如针对式(II)所定义)的化合物,以形成由式(V)表示的药物-接头化合物:
D-(XD)a(C)c(XZ)b-R31 (V)
其中R31为适用于与Z上的互补官能团反应形成缀合物的官能团。适合基团R31的实例包括氨基、叠氮基、硫醇、环辛炔、
其中R32为Cl、Br、F、甲磺酸醋或甲苯磺酸醋,且R33为Cl、Br、I、F、OH、-O-N-琥珀酰亚胺基、-O-(4-硝基苯基)、-O-五氟苯基或-O-四氟苯基。通常可用于制备适合部分D-(XD)aC(XZ)b-R31的化学方法公开于以下中:Ng等人,US 7,087,600 B2(2006);Ng等人,US 6,989,452 B2(2006);Ng等人,US 7,129,261 B2(2006);Ng等人,WO 02/096910 A1;Boyd等人,US7,691,962 B2;Chen等人,US 7,517,903 B2(2009);Gangwar等人,US 7,714,016 B2(2010);Boyd等人,US 2008/0279868 A1;Gangwar等人,US 7,847,105 B2(2010);Gangwar等人,US 7,968,586 B2(2011);Sufi等人,US 8,461,117 B2(2013);和Chen等人,US 8,664,407B2(2014);其公开内容以引用的方式并入本文中。
优选地,反应性官能团-R31为-NH2、-OH、-CO2H、-SH、马来酰亚胺基、环辛炔、叠氮基(-N3)、羟基氨基(-ONH2)或N-羟基琥珀酰亚胺基。尤其优选的官能团-R31为:
-OH基团可用抗体上(例如天冬氨酸或谷氨酸侧链上)的羧基酯化。
-CO2H基团可用抗体上的-OH基团酯化或用抗体上(例如赖氨酸侧链上)的氨基酰胺化。
N-羟基琥珀酰亚胺基为功能上活化的羧基且可便利地通过与氨基(例如赖氨酸的氨基)反应酰胺化。
马来酰亚胺基可与抗体上的-SH基团(例如来自半胱氨酸或来自引入硫氢基官能团的抗体的化学修饰)在迈克尔加成反应中缀合。
若抗体不具有用于缀合的半胱氨酸-SH,则赖氨酸残基侧链中的ε-氨基可与2-亚氨基硫杂环戊烷或N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丙酸酯(“SPDP”)反应以引入游离的硫醇(-SH)基,从而实际上产生半胱氨酸替代物。硫醇基可与马来酰亚胺或其他亲核试剂受体基团反应以实现缀合。下方示出2-亚氨基硫杂环戊烷情形下的机制。
通常,达成每个抗体二至三个硫醇的硫醇化水平。代表性操作参见Cong等人,US8,980,824 B2(2015),其公开内容以引用的方式并入本文中。
在相反配置中,可以用4-(马来酰亚胺基甲基)-环己甲酸N-琥珀酰亚胺基酯(“SMCC”)或其磺化变体磺基-SMCC(该两者可购自Sigma-Aldrich)修饰抗体Z,以向其中引入马来酰亚胺基。随后,可使用接头上具有-SH基团的药物-接头化合物来实现缀合。
替代缀合方法使用无铜“点击化学法(click chemistry)”,其中将叠氮基添加在应变环辛炔上以形成1,2,3-三唑环。参见例如Agard等人,J.Amer.Chem.Soc.2004,126,15046;Best,Biochemistry 2009,48,6571,其公开内容以引用的方式并入本文中。叠氮基可位于抗体上且环辛炔位于药物-接头部分上或反之亦然。优选的环辛炔基为二苯并环辛炔(DIBO)。具有DIBO基团的各种试剂可获自Invitrogen/Molecular Probes,Eugene,Oregon。以下反应说明DIBO基团连接于抗体(Ab)的情况下的点击化学法缀合:
另一缀合技术涉及将非天然氨基酸引入抗体中,其中非天然氨基酸提供用于与药物部分中的反应性官能团缀合的官能团。举例而言,非天然氨基酸对乙酰基苯丙氨酸可并入抗体或其他多肽中,如Tian等人,WO 2008/030612 A2(2008)中所教导。对乙酰基苯丙氨酸中的酮基可经由与接头-药物部分上的羟基氨基形成肟而成为缀合位点。替代地,可将非天然氨基酸对叠氮基苯丙氨酸并入抗体中,得到叠氮基官能团以如上所述经由点击化学法缀合。非天然氨基酸还可使用无细胞方法而并入抗体或其他多肽中,如Goerke等人,US2010/0093024 A1(2010)和Goerke等人,Biotechnol.Bioeng.2009,102(2),400-416中所教示。前述公开内容以引用的方式并入本文中。因此,在一个实施方案中,用于制备缀合物的抗体具有一或多个经非天然氨基酸替换的氨基酸,该非天然氨基酸优选为对乙酰基苯丙氨酸或对叠氮基苯丙氨酸,更优选为对乙酰基苯丙氨酸。
根据Jeger等人,Angew.Chem.Int.Ed.2010,49,9995,另一缀合技术使用谷氨酰胺转氨酶(优选为来自茂源链霉菌(Streptomyces mobaraensis)的细菌性谷氨酰胺转氨酶或BTG)。BTG在谷氨酰胺的侧链甲酰胺(胺受体)与亚烷基氨基(胺供体)(其可为例如赖氨酸的ε-氨基或5-氨基-正戊基)之间形成酰胺键。在典型缀合反应中,如下所示,谷氨酰胺残基位于抗体上,而亚烷基氨基位于接头-药物部分上:
谷氨酰胺残基位于多肽链上对其对BTG介导的转酰胺作用的敏感性具有很大影响。抗体上的谷氨酰胺残基通常均不为BTG底物。然而,若抗体去糖基化,糖基化位点为重链的天冬酰胺297(N297;根据如Kabat等人,“Sequences of proteins of immunologicalinterest”,第5版,公开案第91-3242号,美国健康与人类服务部(U.S.Dept.Health&HumanServices),NIH,Bethesda,Md.,1991;下文简称“Kabat”中所阐述的EU索引编号),则邻近的谷氨酰胺295(Q295)表现为BTG敏感的。抗体可通过用PNGase F(肽-N-糖苷酶F)处理而以酶方式去糖基化。替代地,抗体可通过在恒定区中引入N297A突变而以无糖苷的形式合成,从而去除N297糖基化位点。此外,已证实N297Q取代不仅去除糖基化,且也引入同样为胺受体的第二谷氨酰胺残基(在位置297处)。由此,在一个实施方案中,抗体去糖基化。在另一实施方案中,抗体具有N297Q取代。本领域技术人员将了解,通过合成后修饰或通过引入N297A突变进行的去糖基化使每个抗体产生二个BTG反应性谷氨酰胺残基(每条重链一个,在位置295处),而具有N297Q取代的抗体将具有四个BTG反应性谷氨酰胺残基(每条重链两个,在位置295和297处)。
通过向抗体中引入含有谷氨酰胺的肽或“标签”,抗体也可表现为对BTG介导的缀合敏感,例如Pons等人,US 2013/0230543 A1(2013)和Rao-Naik等人,WO 2016/144608 A1中所教导。
在补充方法中,可通过改变BTG的氨基酸序列而改变其底物特异性,使得其变得能够与未经修饰抗体中的谷氨酰胺295反应,如Rao-Naik等人,WO 2017/059158 A1(2017)中所教导。
虽然最常用的细菌性谷氨酰胺转氨酶为来自茂源链霉菌的细菌性谷氨酰胺转氨酶,但也可考虑来自底物特异性略微不同的其他细菌的谷氨酰胺转氨酶,诸如来自拉达卡链轮丝菌(Streptoverticillium ladakanum)的谷氨酰胺转氨酶(Hu等人,US 2009/0318349 A1(2009)、US 2010/0099610 A1(2010)和US 2010/0087371 A1(2010))。
具有伯或仲烷基胺的本发明TLR7激动剂尤其适合于以缀合物形式使用,因为仲胺提供用于连接接头的官能团。此类TLR7激动剂-接头化合物的实例为化合物22,其含有酶促可裂解接头。图5示出可据其制备化合物22的方案。
含有非酶促可裂解接头的TLR7激动剂-接头化合物的实例为化合物24。
图6示出用于合成化合物24的方案。
化合物22和24均含有伯烷基氨基,使得其能够与谷氨酰胺转氨酶缀合。下文实例中描述适合的缀合操作。
还可使用分选酶A(Sortase A)来实现缀合,如Levary等人,PLoS One2011,6(4),e18342;Proft,Biotechnol.Lett.2010,32,1-10;Ploegh等人,WO 2010/087994 A2(2010);和Mao等人,WO 2005/051976 A2(2005)中所教导。分选酶A识别基序(通常LPXTG,其中X为任何天然氨基酸)可位于配体Z上,且亲核性受体基序(通常GGG)可为式(III)中的基团R31,或反之亦然。
TLR7激动剂缀合物
应用前述技术,可制备TLR7激动剂缀合物,诸如下方所示的缀合物:
其中m为1、2、3或4,且Ab为抗体。
聚乙二醇化
将聚(乙二醇)(PEG)链连接至药物(“聚乙二醇化”)可改善药物的药物动力学特性。药物的循环半衰期增加,有时增加超过一个数量级,同时降低了达成所要治疗效果所需要的剂量。聚乙二醇化还可减少药物的代谢降解且降低其免疫原性。综述参见Kolate等人,J.Controlled Release 2014,192,167。
聚乙二醇化最初应用于生物药物。截至2016年,已批准超过十种聚乙二醇化生物制剂。Turecek等人,J.Pharmaceutical Sci.2016,105,460。最近,受该理论于生物制剂中成功应用的刺激,人们注意力已转向其于小分子药物中的应用。除前述益处外,聚乙二醇化小分子药物可具有增加的溶解度且引起较少毒性作用。Li等人Prog.Polymer Sci.2013,38,421。
本文所公开的化合物可经聚乙二醇化。在化合物具有脂族羟基或脂族伯或仲胺时,诸如化合物Ia-01或Ia-02(箭头)的情形,该化合物可利用常规技术(诸如二环己基碳二亚胺、HATU、N-羟基琥珀酰亚胺酯等)通过含有羧基的PEG分子经由酯基、酰氨基、碳酸酯基或氨基甲酸酯基而聚乙二醇化。用于对药物分子进行聚乙二醇化的各种其他方法公开于Alconcel等人,Polymer Chem.2011,2,1442中,其公开内容以引用的方式并入本文中。
视需要,本文中所公开的TLR7激动剂可经由包含自分解部分的酶促可裂解接头聚乙二醇化,从而允许未经聚乙二醇化的激动剂以设计方式释放。此外,若含有PEG的分子具有用于连接至蛋白的适合官能团(诸如胺),则聚乙二醇化可与该蛋白(诸如抗体)的缀合组合。蛋白可提供额外治疗功能,或在抗体的情况下可提供靶向功能。在下方反应序次中示出这些理论,其中TLR7-NH-R通常表示TLR7激动剂:
在上述反应序次中,缬氨酸-瓜氨酸(Val-Cit)二肽可通过组织蛋白酶B裂解,其中对氨基苯甲基氧基羰基(PABC)充当自分解间隔基。用于缀合的官能团为胺基,其暂时受Fmoc基团保护。缀合由谷氨酰胺转氨酶实现,其中谷氨酰胺(Gln)侧链充当酰基受体。取决于聚乙二醇化的目的,表示PEG重复单元的数目的下标x可广泛变化,如下文所论述。出于一些目的,x可相对较小,诸如2、4、8、12或24。出于其他目的,x较大,例如介于约45至约910之间。
本领域技术人员将理解,该序次为说明性的,且可使用如本领域中所熟知的其他要素(肽、自分解基团、缀合方法、PEG长度等)。本领域技术人员还将理解,虽然上述序次组合聚乙二醇化与缀合,但聚乙二醇化不需要缀合。且反之亦然。
在化合物没有脂族羟基或脂族伯或仲胺时,如在化合物13(图2)的情形中,仍然可在芳胺(箭头)处聚乙二醇化。在该位置处进行聚乙二醇化的方法由Zarraga,US 2017/0166384 A1(2007)公开,其公开内容以引入的方式并入。
在一些实施方案中,可能需要单个分子中连接有多个聚乙二醇化激动剂。举例而言,可在季戊四醇(C(CH2OH)4)上构筑四个聚乙二醇化臂,且TLR7激动剂可连接至各聚乙二醇化臂。参见Gao等人,US 2013/0028857 A1(2013),其公开内容以引用的方式并入。
为了调节药物动力学,通常优选的是PEG部分的分子量介于约2kDa(对应于约45个-(CH2CH2O)-重复单元)至约40kDa(对应于约910个-(CH2CH2O)-重复单元)之间,更优选介于约5kDa至约20kDa之间。即,上式中下标x的范围为约45至约910。应理解,PEG组合物并非100%均质的,而是实际上呈现分子量分布。因此,例如对“20kDa PEG”的提及意指具有20kDa的平均分子量的PEG。
聚乙二醇化还可用于改善激动剂的溶解度。在此类情况下,可使用较短PEG链,例如包含2、4、8、12或24个重复单元。
实施例
可参考以下实施例进一步理解本发明的实践,其以说明方式提供且不意指具有限制性。
实施例1-系列(Ia)和(Ib)化合物
本实施例和图1涉及系列(Ia)和(Ib)化合物的合成,其中化合物(Ib-02)用作范例。
化合物3.将4-羟基苯甲酸甲酯2(2g,13.15mmol)、6-氟吡啶-3-甲醛1(1.809g,14.46mmol)和K2CO3(1.998g,14.46mmol)于DMF(26.3mL)中的悬浮液在110℃搅拌4小时。LCMS指示反应完成。冷却后,用水淬灭反应物,且通过过滤收集所得固体并用水冲洗,且在真空中干燥,得到化合物3(3.30g,12.84mmol,95.1%产率)。LCMS ESI:C14H11NO4的计算值=258.1(M+H+),实验值258.0(M+H+)。1H NMR(400MHz,氯仿-d)δ10.01(s,1H),8.63(d,J=2.4Hz,1H),8.23(dd,J=8.6,2.4Hz,1H),8.17-7.97(m,2H),7.27-7.22(m,2H),7.10(d,J=8.6Hz,1H),3.93(s,3H)
化合物4.在0℃用NaBH4(0.553g,14.62mmol)逐份处理化合物3(3.76g,14.62mmol)于MeOH(100ml)中的溶液,随后在浴液仍处于原位的同时搅拌10分钟。LCMS指示反应完成。通过缓慢添加半饱和NH4Cl淬灭反应物。将反应混合物在RT搅拌30分钟且用EtOAc萃取。有机萃取物经Na2SO4干燥,过滤且浓缩。将粗制固体加入水中制成浆液,并通过过滤收集且在真空中干燥,得到化合物4(3.37g,13.00mmol,89%产率)。LCMS ESI:C14H13NO4的计算值=260.1(M+H+),实验值260.0(M+H+)。1H NMR(400MHz,氯仿-d)δ8.21(d,J=2.2Hz,1H),8.12-8.04(m,2H),7.81(dd,J=8.4,2.4Hz,1H),7.21-7.13(m,2H),6.99(d,J=8.4Hz,1H),4.71(s,2H),3.91(s,3H)
化合物5.用三苯基膦(0.223g,0.849mmol)接着用N-溴琥珀酰亚胺(NBS,0.165g,0.926mmol)处理化合物4(0.2g,0.771mmol)于THF(3.86ml)中的悬浮液。在RT搅拌60分钟后,反应完成。用水淬灭反应物且用EtOAc萃取所得混合物。有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物经12g硅胶柱纯化,用0-80%EtOAc/己烷洗脱,得到化合物5(0.15g,0.466mmol,60.4%产率)。LCMS ESI:C14H12BrNO3的计算值=322.0(M+H+),实验值321.9(M+H+)。1H NMR(400MHz,氯仿-d)δ8.21(d,J=2.4Hz,1H),8.15-8.01(m,2H),7.80(dd,J=8.5,2.5Hz,1H),7.23-7.13(m,2H),6.97(d,J=8.6Hz,1H),4.47(s,2H),3.92(s,3H)。
化合物7.用化合物5(567mg,1.760mmol)处理2-丁氧基-8-甲氧基-9H-嘌呤-6-胺6(CAS登记号866268-31-7,于TFA中,562mg,1.600mmol)和碳酸铯(1.67g,5.12mmol)于DMF(20mL)中的悬浮液。将反应混合物在RT搅拌3小时。LCMS指示反应完成。反应物用饱和NH4Cl淬灭,且用EtOAc萃取。有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物经40g硅胶柱纯化,用20%MeOH/DCM(0-40%梯度)洗脱。浓缩所要级分,得到化合物7(478mg,0.999mmol,62.4%产率)。LCMS ESI:C24H26N6O5的计算值=479.2(M+H+),实验值479.1(M+H+)。1H NMR(400MHz,氯仿-d)δ8.25(d,J=2.2Hz,1H),8.11-8.01(m,2H),7.78(dd,J=8.4,2.4Hz,1H),7.17-7.06(m,2H),6.91(d,J=8.4Hz,1H),5.06(s,2H),4.32(t,J=6.6Hz,2H),4.11(s,3H),3.95-3.84(m,3H),3.49(s,2H),1.89-1.70(m,2H),1.63-1.34(m,2H),0.97(t,J=7.4Hz,3H)
化合物8.在0℃用LiAlH4(1.0M于THF中;1.401mL,1.401mmol)逐滴处理酯7(0.46g,0.934mmol)于THF(10mL)中的经搅拌溶液。搅拌3小时后,LCMS指示反应完成。缓慢添加Na2SO4·10H2O。搅拌1小时后,滤出固体并用MeOH冲洗。浓缩滤液。粗产物经40g硅胶柱纯化,用20%MeOH/DCM(0-40%梯度)洗脱。浓缩所要级分,得到化合物8(363mg,0.806mmol,86%产率)。LCMS ESI:C24H26N6O5的计算值=451.2(M+H+),实验值451.1(M+H+)。1H NMR(400MHz,氯仿-d)δ8.22(d,J=2.2Hz,1H),7.73(dd,J=8.5,2.5Hz,1H),7.40(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,1H),5.82-5.39(m,1H),5.04(s,2H),4.70(s,2H),4.33(t,J=6.7Hz,2H),4.10(s,3H),1.86-1.73(m,2H),1.50(dq,J=15.0,7.5Hz,2H),1.01-0.87(m,3H)
化合物Ib-01.用HCl(1.0M于水中,2mL,2.000mmol)处理化合物8(363mg,0.806mmol)于THF(10mL)中的悬浮液。在60℃搅拌4小时后,LCMS指示反应完成。冷却后,析出白色固体。通过过滤收集白色固体,用水冲洗且在真空中干燥,得到化合物Ib-01(263.6mg,0.598mmol,74.2%产率)。LCMS ESI:C22H24N6O4的计算值=437.2(M+H+),实验值437.1(M+H+)。1H NMR(400MHz,甲醇-d4)δ8.28(d,J=2.4Hz,1H),7.94(dd,J=8.6,2.4Hz,1H),7.42(d,J=8.6Hz,2H),7.08(d,J=8.4Hz,2H),6.94(d,J=8.6Hz,1H),5.06(s,2H),4.63(s,2H),4.54(t,J=6.5Hz,2H),1.99-1.61(m,2H),1.64-1.34(m,2H),1.01(t,J=7.4Hz,3H)。
化合物Ib-02.在RT用亚硫酰氯(0.334mL,4.58mmol)处理化合物Ib-01(100mg,0.229mmol)于THF(10mL)中的溶液,且搅拌3小时后通过LCMS确定反应完成。用DCM共沸移除多余的亚硫酰氯。所得氯甲基化合物不经纯化直接用于下一步骤。
用甲胺(2.0M于THF中,0.165mL,0.330mmol)处理氯甲基化合物(15mg,0.033mmol)于DMF(0.5mL)中的经搅拌溶液,且在RT搅拌隔夜后反应完成。用50%MeOH/DMF稀释反应混合物,且滤出析出的固体。在以下条件下经由制备型LC/MS纯化粗制滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水+10mM乙酸铵;流动相B:95:5乙腈:水+10mM乙酸铵;梯度:经20分钟7-47%B,接着在100%B保持4分钟;流速:20mL/min。合并含有所要产物的级分,且经由离心蒸发干燥,得到化合物Ib-02(3.7mg,7.08μmol,21.47%产率)。LCMSESI:C23H27N7O3的计算值=450.2(M+H+),实验值450.2(M+H+)。1H NMR(500MHz,DMSO-d6)δ8.15(s,1H),7.80(dd,J=8.4,2.0Hz,1H),7.37(d,J=8.2Hz,2H),7.07(d,J=8.3Hz,2H),6.97(d,J=8.5Hz,1H),6.36(s,2H),4.86(s,2H),4.18(t,J=6.6Hz,2H),3.77(s,2H),2.37(s,3H),1.71-1.56(m,2H),1.47-1.34(m,2H),0.92(t,J=7.4Hz,3H)。
大体上遵循前述操作,使用替代胺制备如下表B中所示的其他(Ib)系列化合物。
本领域技术人员将了解,可遵循上述操作但在细节上作必要修改来制备其他化合物。举例而言,化合物
可通过使用酚代替图1方案中的4-羟基苯甲酸甲酯作为起始物质制备。
化合物
可通过完全还原图1的化合物7中的甲酯基团制备。
Ia系列化合物使用4-氟苯甲醛代替图1流程中的6-氟吡啶-3-甲醛且大体上遵循上述操作制备。
如此制得的化合物(Ia)列于表C中。
实施例2-系列(Ic)、(Id)、(Ie)和(IIa)化合物
此实施例和图2涉及系列(Ic)、(Id)、(Ie)和(IIa)化合物的合成,其中化合物(Id-02)用作范例。
除一个步骤外,图2中的步骤与图1中的步骤相同,且上文所描述的先前实施例和操作在细节上作必要修改后可应用于此实施例中。该一个例外为,在第三步骤中制备苯甲基氯化合物12,而非苯甲基溴化合物5(图1中)。下方提供此步骤的详细操作:向化合物11(1.28g,4.92mmol)于DCM(20mL)中的经搅拌溶液中添加DIPEA(0.988mL,5.66mmol),接着在0℃添加Ms-Cl(0.422mL,5.41mmol),接着在RT搅拌16小时后反应完成。反应物用水淬灭且用DCM萃取三次。经合并的有机萃取物经Na2SO4干燥,过滤且浓缩,得到化合物12(1.35g,4.84mmol,98%产率),其不经纯化即用于下一步骤。
表D示出遵循图2的操作且在最终步骤中使用指定胺所制备的(Id)系列化合物。
(Ic)系列化合物除了使用4-羚基苯甲醛和6-氟吡啶甲酸甲醋代替6-氟吡啶-3-甲醛1和5-羟基吡啶甲酸甲酯9作为起始物质外,大体上遵循图2中针对系列(Id)化合物的操作制备。
表E示出以此方式制备的(Ic)系列化合物。
(Ie)系列化合物系除了使用3,4-二氟苯甲醛和4-羟基苯甲酸甲酯代替6-氟吡啶-3-甲醛1和5-羟基吡啶甲酸甲酯9作为起始物质外,大体上遵循图2中针对系列(Id)化合物的操作制备。
表F示出以此方式制备的(Ie)系列化合物。
(IIa)系列化合物除了使用3-氟苯甲醛和3-羟基苯甲酸甲酯代替6-氟吡啶-3-甲醛1和5-羟基吡啶甲酸甲酯9作为起始物质外,大体上遵循图2中针对系列(Id)化合物的操作而制备。
表G示出以此方式制备的(IIa)系列化合物。
实施例3-系列(If)化合物
此实施例和图3涉及系列(If)化合物的合成,其中化合物(If-04)用作范例。
化合物6和化合物16与Cs2CO3偶联,得到化合物17。
用N2对化合物17(1.05g,2.58mmol)、4-氨基苯甲酸甲酯18(0.468g,3.09mmol)、Pd2(dba)3CHCl3加合物(0.264g,0.258mmol)、BINAP(0.321g,0.516mmol)合Cs2CO3(2.52g,7.73mmol)于二噁烷(15mL)中的混合物鼓泡5分钟,随后密封,在100℃搅拌5小时,此后反应完成。用乙酸乙酯稀释反应混合物,且通过过滤去除固体。浓缩滤液。粗产物经ISCO硅胶12g柱纯化,用20%MeOH/DCM(DCM梯度0-20%)洗脱。浓缩所要级分,得到化合物19(342.7mg,0.718mmol,27.8%)。
大体上遵循前述操作和图3的方案,使用表H中所示的胺,用化合物19来制备(If)系列化合物。。
实施例4-系列(Ig)化合物
此实施例和图7涉及化合物Ig-01的制备。
用K2CO3(2.125g,15.38mmol)处理化合物25(CAS登记号1394947-77-3,2.36g,12.81mmol)和化合物1(1.923g,15.38mmol)于DMF(25.6ml)中的混合物,且随后在50℃搅拌隔夜。将反应物用水淬灭且搅拌1小时。通过过滤收集所得乳油状有色固体,且风干,得到化合物26(3.51g,12.13mmol,95%产率)。1H NMR(400MHz,氯仿-d)δ10.03(s,1H),8.69(d,J=2.0Hz,1H),8.36(d,J=0.7Hz,1H),8.21(dd,J=8.6,2.4Hz,1H),7.81(d,J=0.7Hz,1H),7.09(d,J=8.8Hz,1H),1.70-1.65(m,9H)
向化合物26(1.0g,3.46mmol)于DCM(5mL)中的经搅拌混合物中添加TFA(2.66mL,34.6mmol),在RT搅拌5小时后,将反应混合物浓缩至干燥。随后将粗产物溶解在DCM中,且小心地用饱和NaHCO3中和。分离两个层。水层用DCM(2×)反萃取。合并的有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物经ISCO硅胶柱(40g)纯化,用20%MeOH/DCM(DCM梯度0-30%)洗脱。浓缩所要级分,得到化合物27(490mg,2.59mmol,74.9%产率)。LCMS ESI:C9H8N3O2的计算值=190.1(M+H+),实验值190.1(M+H+)。
用K2CO3(231mg,1.670mmol)接着用化合物28(461mg,1.927mmol)处理化合物27(243mg,1.285mmol)于DMF(5mL)中的混合物。将反应混合物在90℃搅拌隔夜。将反应混合物用水淬灭且用乙酸乙酯萃取(3×)。合并的有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物通过ISCO硅胶柱(24g)纯化,用乙酸乙酯/己烷(0-80%梯度)洗脱。浓缩所要级分,得到化合物29(230mg,0.662mmol,51.5%产率)。LCMS ESI:C17H26N3O3Si的计算值=348.2(M+H+),实验值348.2(M+H+)。1H NMR(400MHz,氯仿-d)δ10.01(s,1H),8.65(d,J=2.0Hz,1H),8.20-8.16(m,1H),7.79(s,1H),7.61(s,1H),7.06(d,J=8.6Hz,1H),4.28(t,J=5.2Hz,2H),3.99(t,J=5.1Hz,2H),0.87(s,6H),0.00(d,J=2.9Hz,9H)。
用NaBH4(10.89mg,0.288mmol)处理化合物29(100mg,0.288mmol)于MeOH(3mL)中的溶液,且随后在RT搅拌2小时。将反应混合物用水淬灭且用乙酸乙酯萃取(3×)。合并的有机萃取物经Na2SO4干燥,过滤且浓缩。粗产物通过ISCO硅胶柱(24g)纯化,用乙酸乙酯/己烷(0-100%梯度)洗脱。浓缩所要级分,得到化合物30(70mg,0.200mmol,69.6%产率)。LCMSESI:C17H28N3O3Si的计算值=350.2(M+H+),实验值350.4(M+H+)。1H NMR(400MHz,氯仿-d)δ8.18(d,J=1.8Hz,1H),7.74(dd,J=8.4,2.4Hz,1H),7.68(s,1H),7.51(s,1H),6.94(d,J=8.4Hz,1H),4.69(s,2H),4.22(t,J=5.3Hz,2H),3.98(t,J=5.3Hz,2H),0.88(s,9H),0.03-0.01(m,3H),0.00(s,3H)。
在搅拌下用许尼希碱(Hunig's base)(0.060mL,0.346mmol)处理含化合物30(110mg,0.315mmol)的DCM(3mL),接着在0℃用Ms-Cl(0.026mL,0.330mmol)缓慢处理,接着在RT搅拌14小时。将反应混合物用水淬灭且用DCM萃取(3×)。经合并的有机萃取物经Na2SO4干燥,过滤且浓缩,得到化合物31(110mg,0.353mmol,94%产率),其不经进一步纯化即直接用于下一步骤。LCMS ESI:C17H27ClN3O2Si的计算值=368.1(M+H+),实验值368.2(M+H+)。1HNMR(400MHz,氯仿-d)δ8.21(d,J=2.0Hz,1H),7.80(dd,J=8.6,2.6Hz,1H),7.74(s,1H),7.63(s,1H),7.00(d,J=8.4Hz,1H),4.57(s,2H),4.37-4.28(m,2H),4.05(dd,J=5.5,4.2Hz,2H),0.92(s,9H),0.10(s,6H)。
使用前述实施例的操作但在细节上作必要修改,将化合物31转变为化合物Ig-01。LCMS ESI:C20H25N8O4的计算值=441.2(M+H+),实验值441.0(M+H+)。1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),8.15(d,J=1.8Hz,1H),7.81(s,1H),7.76(dd,J=8.5,2.4Hz,1H),7.41(s,1H),6.97(d,J=8.5Hz,1H),6.48(br s,2H),4.84(s,2H),4.15(t,J=6.6Hz,2H),4.08(t,J=5.6Hz,2H),2.91(br d,J=6.4Hz,2H),1.71-1.54(m,2H),1.46-1.28(m,2H),0.90(t,J=7.3Hz,3H)。
实施例5-TLR7激动剂活性测定
本实施例描述一种用于测定本说明书中所公开的化合物的TLR7激动剂活性的方法。
将经工程化改造的具有人类TLR7分泌的胚胎碱性磷酸酶(SEAP)报导转基因的人类胚胎肾蓝色细胞(HEK-BlueTM TLR细胞;Invivogen)悬浮于非选择性培养基(DMEM高葡萄糖(Invitrogen),其补充有10%胎牛血清(Sigma))中。将HEK-BlueTM TLR7细胞添加至384孔组织培养板中的各孔(每孔15,000个细胞),且在37℃、5%CO2培育16至18小时。将化合物(100nl)施配至含有HEK-BlueTM TLR细胞的孔中,且将经处理细胞在37℃、5%CO2进行培育。处理18小时后,将10微升新制的Quanti-BlueTM试剂(Invivogen)添加至各孔,培育30分钟(37℃,5%CO2),且使用Envision读板器(OD=620nm)来测量SEAP含量。计算半数最大有效浓度值(EC50;诱导测定基线与最大值之间一半反应的化合物浓度)。
图6为展示由此获得的化合物(Ib-02)的数据的代表性图。
实施例6-白介素6诱导测定
本实施例描述一种用于测定本说明书中所公开的化合物的白介素6诱导的方法。
使用ECHO声学液体操作技术将于DMSO中稀释的化合物转移至MatrixTechnologies透明V底384孔盘的各个孔中(每孔25nL)。使用CyBio FeliX液体操作仪将人类全血样品(25μL)添加至各孔。将培养板在培养板震荡器上震荡3分钟,之后在37℃培育反应混合物20小时。随后向各孔中添加Basel RPMI 1640培养基(补充有L-谷氨酰胺)(每孔25μL),之后通过离心(450×g,5分钟,环境温度)自各样品释放出血浆。随后使用FeliX液体操作仪将处理后的血浆样品(3μL)转移至白色浅孔的384孔ProxiPlate(Perkin Elmer)的各个孔中,且使用如制造商PerkinElmer所描述的AlphaLISA技术来测量其白介素6含量。使用数据分析软件来确定化合物EC50值,其中使用平均DMSO值确定基线,且使用最高所测试浓度的参考化合物值确定100%诱导。可使用诸如Graphpad PrismTM的软件确定EC50。
实施例7-谷氨酰胺转氨酶介导的缀合
以下操作可用于谷氨酰胺转氨酶介导的激动剂-接头化合物缀合,其中接头具有可充当胺供体的胺基。抗体可为具有谷氨酰胺转氨酶反应性谷氨酰胺的抗体,例如具有N297A或N297Q取代的抗体。缀合通过重组细菌性谷氨酰胺转氨酶进行,其中抗体:酶的摩尔比为5:1。缀合使用标准方案于50mM Tris缓冲液(pH 8.0)中在37℃培育过夜进行。在用50mM Tris(pH 8.0)预平衡的蛋白A柱上纯化所得缀合物。将缀合物用0.1M柠檬酸钠缓冲液(pH 3.5)洗脱。用1M Tris(pH 9.0)中和洗脱的级分。可在20mg/mL山梨糖醇、10mg/mL甘氨酸(pH 5.0)中调配缀合物。
本领域技术人员将理解,本实施例中的条件和方法为说明性且非限制性的,且其变化形式或其他缀合方法为本领域中已知的且可用于本发明中。
本发明的前述详细描述包括主要或仅涉及本发明的特定部分或方面的段落。应了解,出于明晰和便利的目的,特定特征可不仅在公开该特征的段落中相关,且本文的公开内容包括不同段落中存在的信息的所有适当组合。类似地,尽管本文的各种图和描述涉及本发明的特定实施方案,但应了解,若特定特征公开于特定图或实施方案的情形下,则此类特征通常还可以适当程度与另一特征组合用于另一图或实施方案的情形下或本发明中。
此外,尽管本发明尤其关于某些优选实施方案进行描述,但本发明并不限于此类优选实施方案。确切而言,本发明的范围通过所附权利要求书界定。
参考文献
下文提供以下参考文献的完整引用,之前在本说明书中这些参考文献以简化方式以第一作者(或发明者)和日期形式引用。这些参考文献各自以引用的方式并入本文中以用于所有目的。
Akinbobuyi et al.,ACS 2013 69th Southwest Regional Meeting,AbstractSWRM-70,“Synthesis and evaluation of purine-based toll-like receptor7agonists and their antibody conjugates.”
Akinbobuyi et al.,ACS 2015Joint Southeastern/Southwest RegionalMeeting,Abstract 392,“Synthesis of functionalized purine analogs for antibodyconjugation”[2015a].
Akinbobuyi et al.,Tetrahedron Lett.2015,56,458,“Facile syntheses offunctionalized toll-like receptor 7agonists”[2015b].
Akinbobuyi et al.,Bioorg.Med.Chem.Lett.2016,26,4246,“Synthesis andimmunostimulatory activity of substituted TLR7 agonists.”
Barberis et al.,US 2012/0003298A1(2012).
Beesu et al.,J.Med.Chem.2017,60,2084,“Identification of High-PotencyHuman TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines.”
et al.,J.Immunol.2007,178,4072,“Natural and SyntheticTLR7Ligands Inhibit CpG-A-and CpG-C-Oligodeoxynucleotide-Induced IFN-αProduction.”
Bonfanti et al.,US 2014/0323441 A1(2015)[2015a].
Bonfanti et al.,US 2015/0299221 A1(2015)[2015b].
Carson et al.,US 2013/0202629 A1(2013).
Carson et al.,US 8,729,088 B2(2014).
Carson et al.,US 9,050,376 B2(2015).
Carson et al.,US 2016/0199499 A1(2016).
Chan et al.,Bioconjugate Chem.2009,20,1194,“Synthesis andImmunological Characterization of Toll-Like Receptor 7Agonistic Conjugates.”
Chan et al.,Bioconjugate Chem.2011,22,445,“Synthesis andCharacterization of PEGylated Toll Like Receptor 7 Ligands.”
Cortez et al.,US 2017/0044168 A1(2017).[2017a].
Cortez et al.,US 2017/0121421 A1(2017).[2017b].
Desai et al.,US 9,127,006 B2(2015).
Ding et al.,WO 2016/107536 A1(2016).
Ding et al.,US 2017/0273983 A1(2017)[2017a].
Ding et al.,WO 2017/076346 A1(2017)[2017b].
Gadd et al.,Bioconjugate Chem.2015,26,1743,“Targeted Activation ofToll-Like Receptors:Conjugation of a Toll-Like Receptor 7 Agonist to aMonoclonal Antibody Maintains Antigen Binding and Specificity.”
Graupe et al.,US 8,993,755 B2(2015).
Halcomb et al.,US 9,161,934 B2(2015).
Hashimoto et al.,US 2009/0118263 A1(2009).
Hirota et al.,US 6,028,076(2000).
Holldack et al.,US 2012/0083473 A1(2012).
Isobe et al.,US 6,376,501 B1(2002).
Isobe et al.,JP 2004137157(2004).
Isobe et al.,J.Med.Chem.2006,49(6),2088,“Synthesis and BiologicalEvaluation of Novel 9-Substituted-8-Hydroxyadenine Derivatives as PotentInterferon Inducers.”
Isobe et al.,US 7,521,454 B2(2009)[2009a].
Isobe et al.,US 2009/0105212 A1(2009)[2009b].
Isobe et al.,US 2011/0028715 A1(2011).
Isobe et al.,US 8,148,371 B2(2012).
Jensen et al.,WO 2015/036044 A1(2015).
Kasibhatla et al.,US 7,241,890 B2(2007).
Koga-Yamakawa et al.,Int.J.Cancer 2013,132(3),580,“Intratracheal andoral administration of SM-276001:A selective TLR7 agonist,leads to antitumorefficacy in primary and metastatic models of cancer.”
Li et al.,US 9,902,730 B2(2018).
Lioux et al.,US 9,295,732 B2(2016).
Lund et al.,Proc.Nat’l Acad.Sci(USA)2004,101(15),5598,“Recognition ofsingle-stranded RNA viruses by Toll-like receptor 7.”
Maj et al.,US 9,173,935 B2(2015).
McGowan et al.,J.Med.Chem.2017,60,6137,“Identification andOptimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7(TLR7)SelectiveAgonists for the Treatment of Hepatitis B.”
Musmuca et al.,J.Chem.Information&Modeling 2009,49(7),1777,“Small-Molecule Interferon Inducers.Toward the Comprehension of theMolecularDeterminants through Ligand-Based Approaches.”
Ogita et al.,US 2007/0225303 A1(2007).
Peterson,Rachel;Honor Program Thesis,“Synthesis of Sulfur and Amino-8-Substituted Adenine Derivatives as TLR7 Agonists,”Baylor University (2014).
Pryde,US 7,642,350 B2(2010).
Roethle et al.,J.Med.Chem 2013,56,7324,“Identification andOptimization of Pteridinone Toll-like Receptor 7(TLR7)Agonists for the OralTreatment of Viral Hepatitis.”
Seifert,Zacharie;Master of Science Thesis,“Synthesis and Evaluationof 8-Substituted Adenine Derivatives as Toll-like Receptor 7 Agonists,”BaylorUniversity(2015).
Vernejoul et al.,US 2014/0141033 A1(2014).
Yu et al.,PLoS One 2013,8(3),e56514,“Toll-Like Receptor 7 Agonists:Chemical Feature Based Pharmacophore Identification and Molecular DockingStudies.”
Zhang et al.,Immunity 2016,45,737,“Structural Analysis Reveals thatToll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-StrandedRNA.”
Zurawski et al.,US 2012/0231023 A1(2012).
Claims (22)
1.一种化合物,其由式(I)或式(II)表示
其中
R1为(C1-C5烷基)O、(C1-C2烷基)O(CH2)2-3O、(C1-C5烷基)C(=O)O、(C1-C5烷基)NH、(C1-C2烷基)O(CH2)2-3NH或(C1-C5烷基)C(=O)NH;
R2在每次出现时独立地为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN或NO2;
X在每次出现时独立地为CR2或N;
R3为O、S、NH或N(C1-C3烷基);
Ar为
其中Y、Y'和Y”中的一个选自-O-、-S-、-NH-和-N(C1-C3烷基)-,且Y、Y'和Y”中的另外两个选自=N-和=CR2-;
R4为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN、NO2或(CH2)xR5,其中下标x为1、2、3或4;且
R5为H、卤素、OH、CN、NH2、NH(C1-C5烷基)、N(C1-C5烷基)2、NH(C3-C6环烷基)、NH(C4-C8双环烷基)、NH(C6-C10螺环烷基)、N(C3-C6环烷基)2、NH(CH2)1-3(芳基)、N((CH2)1-3(芳基))2或者具有结构的环胺基团,其中所述芳基为具有单环环系统的烃部分,其中所述环具有3至7个碳原子且所述环为芳香族;
其中
烷基、环烷基、双环烷基、螺环烷基或者环胺任选地经一或多个选自以下的取代基取代:OH、卤素、CN、C1-C3烷基、O(C1-C3烷基)、C(=O)(Me)、SO2(C1-C3烷基)、C(=O)(Et)、NH2、NH(Me)、NH(Et)和N(C1-C3烷基)2;且
环烷基、双环烷基、螺烷基或环胺基团可具有经O、S、NH、N(C1-C3烷基)或N(Boc)替换的CH2基团。
2.根据权利要求1所述的化合物,其由式(I')表示
其中各X'独立地为CH或N。
3.根据权利要求2所述的化合物,其中R4为CH2R5且R5为OH、Cl、
4.根据权利要求1所述的化合物,其由式(Ia)表示
5.根据权利要求4所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
6.根据权利要求1所述的化合物,其由式(Ib)表示
7.根据权利要求6所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
8.根据权利要求1所述的化合物,其由式(Ic)表示
9.根据权利要求8所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
10.根据权利要求1所述的化合物,其由式(Id)表示
11.根据权利要求10所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
12.根据权利要求1所述的化合物,其由式(Ie)表示
13.根据权利要求12所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
14.根据权利要求1所述的化合物,其由式(If)表示
15.根据权利要求14所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
16.根据权利要求1所述的化合物,其由式(IIa)表示
17.根据权利要求16所述的化合物,其中R1为n-BuO,x为1且R5为OH、Cl、
18.根据权利要求1或6所述的化合物,其具有由式(Ig)表示的结构:
19.根据权利要求1或6所述的化合物,其中所述化合物为
20.根据权利要求1或6所述的化合物,其中所述化合物为
21.根据权利要求1所述的化合物,其中烷基、环烷基、双环烷基、螺环烷基或者环胺任选地经一或多个选自以下的取代基取代:OH、卤素、CN、C1-C3烷基、O(C1-C3烷基)、C(=O)(Me)、SO2(C1-C3烷基)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)和N(Et)2。
22.根据权利要求1至21中任一项所述的化合物在制备用于治疗适合于通过活化Toll样受体7治疗的病状的药物中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762546222P | 2017-08-16 | 2017-08-16 | |
US62/546,222 | 2017-08-16 | ||
PCT/US2018/000246 WO2019035971A1 (en) | 2017-08-16 | 2018-08-16 | 6-AMINO-7,9-DIHYDRO-8H-PURIN-8-ONE DERIVATIVES AS TOLL 7 RECEPTOR IMMUNOSTIMULATING AGONISTS (TLR7) |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111201228A CN111201228A (zh) | 2020-05-26 |
CN111201228B true CN111201228B (zh) | 2024-04-09 |
Family
ID=63528885
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880065815.4A Active CN111201228B (zh) | 2017-08-16 | 2018-08-16 | 作为Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 |
Country Status (17)
Country | Link |
---|---|
US (4) | US10508115B2 (zh) |
EP (1) | EP3668871B1 (zh) |
JP (1) | JP7228570B2 (zh) |
KR (1) | KR20200041910A (zh) |
CN (1) | CN111201228B (zh) |
AR (1) | AR112689A1 (zh) |
AU (1) | AU2018317860A1 (zh) |
BR (1) | BR112020003108A2 (zh) |
CA (1) | CA3073013A1 (zh) |
CO (1) | CO2020001498A2 (zh) |
EA (1) | EA202090495A1 (zh) |
ES (1) | ES2887253T3 (zh) |
IL (1) | IL272626A (zh) |
MX (1) | MX2020001734A (zh) |
SG (1) | SG11202001255WA (zh) |
TW (1) | TW201920181A (zh) |
WO (1) | WO2019035971A1 (zh) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109843327B (zh) | 2016-07-07 | 2022-05-13 | 小利兰·斯坦福大学托管委员会 | 抗体佐剂缀合物 |
US11485741B2 (en) | 2018-04-24 | 2022-11-01 | Bristol-Myers Squibb Company | Macrocyclic toll-like receptor 7 (TLR7) agonists |
US11554120B2 (en) | 2018-08-03 | 2023-01-17 | Bristol-Myers Squibb Company | 1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists and methods and uses therefor |
CN113164618A (zh) | 2018-09-12 | 2021-07-23 | 希沃尔拜克治疗公司 | 用免疫刺激性缀合物治疗疾病的方法和组合物 |
BR112021010060B1 (pt) | 2018-11-30 | 2024-03-12 | Bristol-Myers Squibb Company | Anticorpo que compreende uma extensão c-terminal de cadeia leve que contém glutamina, conjugados do mesmo, e método de preparação de conjugados |
EP3894443A2 (en) | 2018-12-12 | 2021-10-20 | Bristol-Myers Squibb Company | Antibodies modified for transglutaminase conjugation, conjugates thereof, and methods and uses |
JP7287708B2 (ja) | 2019-02-08 | 2023-06-06 | プロジェニア インコーポレイテッド | Toll-like受容体7または8アゴニストとコレステロールの結合体およびその用途 |
JP2022525594A (ja) | 2019-03-15 | 2022-05-18 | ボルト バイオセラピューティクス、インコーポレーテッド | Her2を標的とする免疫結合体 |
WO2021058027A1 (zh) * | 2019-09-29 | 2021-04-01 | 江苏恒瑞医药股份有限公司 | 吡咯并杂芳基衍生物或其偶联物、其制备方法及其应用 |
AU2020358726A1 (en) | 2019-10-01 | 2022-04-07 | Silverback Therapeutics, Inc. | Combination therapy with immune stimulatory conjugates |
KR20220132589A (ko) | 2020-01-27 | 2022-09-30 | 브리스톨-마이어스 스큅 컴퍼니 | 톨-유사 수용체 7 (TLR7) 효능제로서의 1H-피라졸로[4,3-d]피리미딘 화합물 |
US20230144824A1 (en) | 2020-01-27 | 2023-05-11 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
US20230127326A1 (en) * | 2020-01-27 | 2023-04-27 | Bristol-Myers Squibb Company | C3-SUBSTITUTED 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
US20230041738A1 (en) * | 2020-01-27 | 2023-02-09 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
US20230122249A1 (en) | 2020-01-27 | 2023-04-20 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
US20230140430A1 (en) | 2020-01-27 | 2023-05-04 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
CN115151548A (zh) * | 2020-01-27 | 2022-10-04 | 百时美施贵宝公司 | 作为Toll样受体7(TLR7)激动剂的1H-吡唑并[4,3-d]嘧啶化合物 |
KR20220132592A (ko) | 2020-01-27 | 2022-09-30 | 브리스톨-마이어스 스큅 컴퍼니 | 톨-유사 수용체 7 (TLR7) 효능제로서의 1H-피라졸로[4,3-d]피리미딘 화합물 |
WO2021154665A1 (en) | 2020-01-27 | 2021-08-05 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS |
JP2023514727A (ja) | 2020-02-21 | 2023-04-07 | シルバーバック セラピューティックス インコーポレイテッド | ネクチン-4抗体コンジュゲートおよびその使用 |
AU2021231160A1 (en) | 2020-03-02 | 2022-09-22 | Progeneer Inc. | Live-pathogen-mimetic nanoparticles based on pathogen cell wall skeleton, and production method thereof |
CN113797354B (zh) * | 2020-06-11 | 2024-08-13 | 江苏恒瑞医药股份有限公司 | 吡咯并嘧啶衍生物或其偶联物、其制备方法及其应用 |
JP2023532304A (ja) | 2020-07-01 | 2023-07-27 | エーアールエス ファーマシューティカルズ オペレーションズ,インク. | 抗asgr1抗体コンジュゲートおよびその使用 |
EP4194008A1 (en) | 2020-08-04 | 2023-06-14 | Progeneer Inc. | Kinetically acting adjuvant ensemble |
CN116056725A (zh) | 2020-08-04 | 2023-05-02 | 蛋白科技先鋒 | 活性位点暂时灭活的功能性药物与Toll样受体7或8激动剂的缀合物及其用途 |
US20230346924A1 (en) | 2020-08-04 | 2023-11-02 | Progeneer Inc. | Mrna vaccine comprising adjuvant capable of kinetic control |
US20240124486A1 (en) * | 2020-09-27 | 2024-04-18 | Shanghai Visonpharma Co., Ltd. | Macrocyclic tlr7 agonist, preparation method therefor, pharmaceutical composition and use thereof |
CA3196221A1 (en) | 2020-10-21 | 2022-04-28 | Univerza V Ljubljani | Conjugated tlr7 and nod2 agonists |
WO2022161420A1 (zh) * | 2021-01-28 | 2022-08-04 | 上海翊石医药科技有限公司 | 一类芳杂环类化合物及其制备方法和用途 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1921862A (zh) * | 2003-12-19 | 2007-02-28 | 赛诺菲巴斯德有限公司 | 包含至少一种toll样受体7或toll样受体8激动剂以及toll样受体4激动剂的免疫刺激组合物 |
EP2133353A1 (en) * | 2007-03-20 | 2009-12-16 | Dainippon Sumitomo Pharma Co., Ltd. | Novel adenine compound |
CN102905726A (zh) * | 2010-06-03 | 2013-01-30 | 葛兰素史密丝克莱恩生物有限公司 | 包含抗原和Toll样受体激动剂的口服疫苗 |
CA2866404A1 (en) * | 2012-03-05 | 2013-09-12 | Duke University | Vaccine formulation |
WO2015095780A1 (en) * | 2013-12-20 | 2015-06-25 | The University Of Kansas | Toll-like receptor 8 agonists |
WO2016057618A1 (en) * | 2014-10-09 | 2016-04-14 | Wake Forest University Health Sciences | Vaccine compositions and methods of use to treat neonatal subjects |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
US4698420A (en) | 1985-02-25 | 1987-10-06 | Xoma Corporation | Antibody hybrid molecules and process for their preparation |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
WO1998001448A1 (fr) | 1996-07-03 | 1998-01-15 | Japan Energy Corporation | Nouveaux derives de purine |
TW572758B (en) | 1997-12-22 | 2004-01-21 | Sumitomo Pharma | Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives |
US7425541B2 (en) | 1998-12-11 | 2008-09-16 | Medarex, Inc. | Enzyme-cleavable prodrug compounds |
NZ517202A (en) | 1999-08-24 | 2004-05-28 | Medarex Inc | Human CTLA-4 antibodies and their uses |
WO2002015700A1 (en) | 2000-08-24 | 2002-02-28 | Coulter Pharmaceutical, Inc. | Prodrugs activated by plasmin and their use in cancer chemotherapy |
WO2002085905A1 (fr) | 2001-04-17 | 2002-10-31 | Sumitomo Pharmaceuticals Company, Limited | Nouveaux derives d'adenine |
EP2266986A1 (en) | 2001-05-31 | 2010-12-29 | Medarex, Inc. | Cytotoxins, Prodrugs, Linkers and Stabilizers useful therefor |
CA2450316A1 (en) | 2001-06-11 | 2002-12-19 | Medarex, Inc. | Cd10-activated prodrug compounds |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
EP2336133A1 (en) | 2001-10-30 | 2011-06-22 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
IL162835A0 (en) | 2002-01-09 | 2005-11-20 | Medarex Inc | Human monoclonal antibodies against cd30 |
BR0314761A (pt) | 2002-09-27 | 2005-07-26 | Sumitomo Pharma | Composto de adenina e seu uso |
JP2004137157A (ja) | 2002-10-16 | 2004-05-13 | Sumitomo Pharmaceut Co Ltd | 新規アデニン誘導体を有効成分として含有する医薬 |
ES2340494T3 (es) | 2003-04-15 | 2010-06-04 | Glaxosmithkline Llc | Mutantes de sustitucion de il-18 humana y sus conjugados. |
KR101215218B1 (ko) | 2003-07-22 | 2012-12-26 | 바이엘 파마 악티엔게젤샤프트 | Rg1 항체 및 그의 용도 |
WO2005051976A2 (en) | 2003-11-20 | 2005-06-09 | Ansata Therapeutics, Inc. | Protein and peptide ligation processes and one-step purification processes |
RS53984B1 (en) | 2003-12-10 | 2015-10-30 | E. R. Squibb & Sons L.L.C. | IP-10 ANTIBODIES AND THEIR USES |
EP1718667B1 (en) | 2004-02-23 | 2013-01-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
AU2005227326B2 (en) | 2004-03-24 | 2009-12-03 | Xencor, Inc. | Immunoglobulin variants outside the Fc region |
US20070225303A1 (en) | 2004-03-26 | 2007-09-27 | Haruhisa Ogita | 8-Oxoadenine Compound |
US7691962B2 (en) | 2004-05-19 | 2010-04-06 | Medarex, Inc. | Chemical linkers and conjugates thereof |
EP1747021B1 (en) | 2004-05-19 | 2015-09-09 | E. R. Squibb & Sons, L.L.C. | Self-immolative linkers and drug conjugates |
DK1791565T3 (en) | 2004-09-23 | 2016-08-01 | Genentech Inc | Cysteingensplejsede antibodies and conjugates |
WO2006089230A2 (en) | 2005-02-18 | 2006-08-24 | Medarex, Inc. | Human monoclonal antibodies to prostate specific membrane antigen (psma) |
RU2421466C2 (ru) | 2005-02-18 | 2011-06-20 | Медарекс, Инк. | Выделенное антитело против специфического мембранного антигена простаты (psma) и способ ингибирования роста клеток, экспрессирующих psma |
US7714016B2 (en) | 2005-04-08 | 2010-05-11 | Medarex, Inc. | Cytotoxic compounds and conjugates with cleavable substrates |
MX2007013780A (es) | 2005-05-04 | 2008-02-05 | Pfizer Ltd | Derivados 2 amido-6-amino-8-oxo purina como moduladores del receptor como tipo peaje (toll) para el tratamiento del cancer y las infecciones virales tal como la hepatitis c. |
EP3530736A3 (en) | 2005-05-09 | 2019-11-06 | ONO Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics |
EA200800094A1 (ru) | 2005-06-20 | 2008-06-30 | Медарекс, Инк. | Антитела cd19 и их использование |
WO2007005874A2 (en) | 2005-07-01 | 2007-01-11 | Medarex, Inc. | Human monoclonal antibodies to programmed death ligand 1 (pd-l1) |
WO2007011968A2 (en) | 2005-07-18 | 2007-01-25 | Seattle Genetics, Inc. | Beta-glucuronide-linker drug conjugates |
EP1939201A4 (en) | 2005-09-22 | 2010-06-16 | Dainippon Sumitomo Pharma Co | NEW ADENINE CONNECTION |
EP1939199A4 (en) * | 2005-09-22 | 2010-10-20 | Dainippon Sumitomo Pharma Co | NEW ADENINE CONNECTION |
US20090118263A1 (en) | 2005-09-22 | 2009-05-07 | Dainippon Sumitomo Pharma Co., Ltd. | Novel Adenine Compound |
EP1940470B1 (en) | 2005-09-26 | 2013-04-17 | Medarex, Inc. | Antibody-drug conjugates and their use |
ES2527961T3 (es) | 2005-09-26 | 2015-02-02 | Medarex, L.L.C. | Anticuerpos monoclonales humanos para CD70 |
EP1940789B1 (en) | 2005-10-26 | 2011-11-23 | Medarex, Inc. | Methods and compounds for preparing cc-1065 analogs |
WO2007059404A2 (en) | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
CA2630483C (en) | 2005-12-08 | 2015-05-19 | Medarex, Inc. | Human monoclonal antibodies to o8e |
JP5401639B2 (ja) | 2005-12-08 | 2014-01-29 | メダレックス エル.エル.シー. | タンパク質チロシンキナーゼ7(ptk7)に対するヒトモノクローナル抗体およびそれらの使用 |
US8715958B2 (en) | 2006-06-29 | 2014-05-06 | The Board Of Trustees Of The Leland Stanford Junior University | Cell-free synthesis of proteins containing unnatural amino acids |
EP2054435A1 (en) | 2006-08-18 | 2009-05-06 | Novo Nordisk Health Care AG | Transglutaminase variants with improved specificity |
CN104328086A (zh) | 2006-09-08 | 2015-02-04 | Ambrx公司 | 通过脊椎动物细胞位点特异性并入非天然氨基酸 |
ME02269B (me) | 2006-10-02 | 2016-04-28 | Medarex Inc | Humana antitela koja se vezuju za cxcr4 i njihove upotrebe |
NZ578064A (en) | 2006-12-01 | 2012-01-12 | Medarex Inc | Human antibodies that bind cd22 and uses thereof |
US7815804B2 (en) | 2006-12-12 | 2010-10-19 | Otv Sa S.A. | Method for treating wastewater or produced water |
UY30776A1 (es) | 2006-12-21 | 2008-07-03 | Medarex Inc | Anticuerpos cd44 |
TWI412367B (zh) | 2006-12-28 | 2013-10-21 | Medarex Llc | 化學鏈接劑與可裂解基質以及其之綴合物 |
BRPI0807196A2 (pt) | 2007-02-07 | 2014-06-03 | Univ California | Método para prevenir ou inibir uma infecção bacteriana, vacina, composto, e, método para prevenir, tratar ou inibir a asma |
US8664407B2 (en) | 2007-02-21 | 2014-03-04 | Medarex, LLC | Chemical linkers with single amino acids and conjugates thereof |
US20100087371A1 (en) | 2007-02-22 | 2010-04-08 | Sean Hu | Transglutaminase Variants with Improved Specificity |
CN101784548B (zh) | 2007-06-29 | 2013-07-17 | 吉里德科学公司 | 嘌呤衍生物及其作为toll样受体7的调节剂的用途 |
WO2009026274A1 (en) | 2007-08-22 | 2009-02-26 | Medarex, Inc. | Site-specific attachment of drugs or other agents to engineered antibodies with c-terminal extensions |
PL2195017T3 (pl) | 2007-10-01 | 2015-03-31 | Bristol Myers Squibb Co | Ludzkie antyciała, które wiążą mezotelinę i ich zastosowania |
CN103497192B (zh) | 2008-12-09 | 2015-09-23 | 吉里德科学公司 | Toll样受体调节剂 |
EP2391714B2 (en) | 2009-01-30 | 2019-07-24 | Whitehead Institute for Biomedical Research | Methods for ligation and uses thereof |
BRPI1008383A2 (pt) | 2009-02-11 | 2016-02-23 | Univ California | composto, composição farmacêutica, método para prevenir, inibir ou tratar uma condição, e, uso de um composto |
AP3103A (en) | 2009-10-22 | 2015-01-31 | Gilead Sciences Inc | Derivatives of purine or deazapurine useful for the treatment of (inter alia)viral infections |
AU2011247358B2 (en) | 2010-04-30 | 2014-10-30 | Urogen Pharma Ltd. | Phospholipid drug analogs |
CN103118682A (zh) | 2010-04-30 | 2013-05-22 | 加利福尼亚大学校务委员会 | 合成tlr7激动剂的磷脂缀合物的用途 |
US20120003298A1 (en) | 2010-04-30 | 2012-01-05 | Alcide Barberis | Methods for inducing an immune response |
US20120083473A1 (en) | 2010-09-21 | 2012-04-05 | Johanna Holldack | Treatment of conditions by toll-like receptor modulators |
CA2930801C (en) | 2010-11-05 | 2019-05-28 | Rinat Neuroscience Corporation | Engineered polypeptide conjugates and methods for making thereof using transglutaminase |
AR085633A1 (es) | 2011-03-08 | 2013-10-16 | Baylor Res Inst | Coadyuvantes basados en anticuerpos que son dirigidos directamente a las celulas presentadoras en antigenos |
WO2013019658A2 (en) | 2011-07-29 | 2013-02-07 | Selecta Biosciences, Inc. | Synthetic nanocarriers comprising polymers comprising multiple immunomodulatory agents |
PT2776439T (pt) | 2011-11-09 | 2018-11-02 | Janssen Sciences Ireland Uc | Derivados de purina para o tratamento de infeções virais |
PT2872515T (pt) | 2012-07-13 | 2016-07-27 | Janssen Sciences Ireland Uc | Purinas macrocíclicas para o tratamento de infeções virais |
EP2732825B1 (en) | 2012-11-19 | 2015-07-01 | Invivogen | Conjugates of a TLR7 and/or TLR8 agonist and a TLR2 agonist |
WO2014126836A1 (en) | 2013-02-14 | 2014-08-21 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
US9295732B2 (en) | 2013-02-22 | 2016-03-29 | Invivogen | Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists |
US20160199499A1 (en) | 2013-08-16 | 2016-07-14 | The Regents Of The University Of California | Uses of phospholipid conjugates of synthetic tlr7 agonists |
WO2015036044A1 (en) | 2013-09-13 | 2015-03-19 | Telormedix Sa | Cationic lipid vehicles for delivery of tlr7 agonists for specific targeting of human cd14+ monocytes in whole blood |
CN106459058B (zh) | 2014-05-01 | 2019-07-05 | 诺华股份有限公司 | 作为toll-样受体7激动剂的化合物和组合物 |
MX362341B (es) | 2014-05-01 | 2019-01-11 | Novartis Ag | Compuestos y composiciones como agonistas del receptor tipo toll 7. |
CN106661034B (zh) | 2014-08-15 | 2019-11-29 | 正大天晴药业集团股份有限公司 | 作为tlr7激动剂的吡咯并嘧啶化合物 |
CN105732635A (zh) | 2014-12-29 | 2016-07-06 | 南京明德新药研发股份有限公司 | 一类Toll样受体7激动剂 |
ES2736106T3 (es) | 2015-03-10 | 2019-12-26 | Bristol Myers Squibb Co | Anticuerpos que se pueden conjugar mediante la transglutaminasa y conjugados producidos a partir de ellos |
KR20180055889A (ko) | 2015-10-02 | 2018-05-25 | 브리스톨-마이어스 스큅 컴퍼니 | 항체를 접합시키기 위한 트랜스글루타미나제 변이체 |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
US10676478B2 (en) | 2015-11-05 | 2020-06-09 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | 7-(thiazol-5-yl) pyrrolopyrimidine compound as TLR7 agonist |
US20170166384A1 (en) | 2015-12-11 | 2017-06-15 | Graphic Packaging International, Inc. | Container with absorption features |
-
2018
- 2018-08-14 US US16/103,619 patent/US10508115B2/en active Active
- 2018-08-15 TW TW107128399A patent/TW201920181A/zh unknown
- 2018-08-15 AR ARP180102341 patent/AR112689A1/es unknown
- 2018-08-16 WO PCT/US2018/000246 patent/WO2019035971A1/en unknown
- 2018-08-16 SG SG11202001255WA patent/SG11202001255WA/en unknown
- 2018-08-16 MX MX2020001734A patent/MX2020001734A/es unknown
- 2018-08-16 BR BR112020003108-9A patent/BR112020003108A2/pt not_active IP Right Cessation
- 2018-08-16 JP JP2020509061A patent/JP7228570B2/ja active Active
- 2018-08-16 EA EA202090495A patent/EA202090495A1/ru unknown
- 2018-08-16 KR KR1020207007180A patent/KR20200041910A/ko not_active Application Discontinuation
- 2018-08-16 ES ES18766418T patent/ES2887253T3/es active Active
- 2018-08-16 AU AU2018317860A patent/AU2018317860A1/en not_active Abandoned
- 2018-08-16 EP EP18766418.0A patent/EP3668871B1/en active Active
- 2018-08-16 CN CN201880065815.4A patent/CN111201228B/zh active Active
- 2018-08-16 CA CA3073013A patent/CA3073013A1/en not_active Abandoned
-
2019
- 2019-11-07 US US16/676,870 patent/US10689382B2/en active Active
-
2020
- 2020-02-11 CO CONC2020/0001498A patent/CO2020001498A2/es unknown
- 2020-02-12 IL IL272626A patent/IL272626A/en unknown
- 2020-05-01 US US16/865,009 patent/US10793569B2/en active Active
- 2020-08-26 US US17/003,385 patent/US10913741B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1921862A (zh) * | 2003-12-19 | 2007-02-28 | 赛诺菲巴斯德有限公司 | 包含至少一种toll样受体7或toll样受体8激动剂以及toll样受体4激动剂的免疫刺激组合物 |
EP2133353A1 (en) * | 2007-03-20 | 2009-12-16 | Dainippon Sumitomo Pharma Co., Ltd. | Novel adenine compound |
CN102905726A (zh) * | 2010-06-03 | 2013-01-30 | 葛兰素史密丝克莱恩生物有限公司 | 包含抗原和Toll样受体激动剂的口服疫苗 |
CA2866404A1 (en) * | 2012-03-05 | 2013-09-12 | Duke University | Vaccine formulation |
WO2015095780A1 (en) * | 2013-12-20 | 2015-06-25 | The University Of Kansas | Toll-like receptor 8 agonists |
WO2016057618A1 (en) * | 2014-10-09 | 2016-04-14 | Wake Forest University Health Sciences | Vaccine compositions and methods of use to treat neonatal subjects |
Also Published As
Publication number | Publication date |
---|---|
MX2020001734A (es) | 2020-03-20 |
US10793569B2 (en) | 2020-10-06 |
AU2018317860A1 (en) | 2020-04-02 |
US10913741B2 (en) | 2021-02-09 |
EA202090495A1 (ru) | 2020-05-28 |
IL272626A (en) | 2020-03-31 |
CN111201228A (zh) | 2020-05-26 |
CA3073013A1 (en) | 2019-02-21 |
US20200255429A1 (en) | 2020-08-13 |
SG11202001255WA (en) | 2020-03-30 |
JP7228570B2 (ja) | 2023-02-24 |
US20190055247A1 (en) | 2019-02-21 |
ES2887253T3 (es) | 2021-12-22 |
CO2020001498A2 (es) | 2020-02-28 |
US20200392137A1 (en) | 2020-12-17 |
JP2020531466A (ja) | 2020-11-05 |
EP3668871A1 (en) | 2020-06-24 |
TW201920181A (zh) | 2019-06-01 |
US10508115B2 (en) | 2019-12-17 |
BR112020003108A2 (pt) | 2020-08-04 |
EP3668871B1 (en) | 2021-08-04 |
US20200095248A1 (en) | 2020-03-26 |
AR112689A1 (es) | 2019-11-27 |
US10689382B2 (en) | 2020-06-23 |
KR20200041910A (ko) | 2020-04-22 |
WO2019035971A1 (en) | 2019-02-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111201228B (zh) | 作为Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 | |
CN111225918B (zh) | 具有三环部分的Toll样受体7(TLR7)激动剂、其缀合物及其方法和用途 | |
US10941145B2 (en) | Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor | |
US10919895B2 (en) | Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |