CN102264394B - 脂化咪唑并喹啉衍生物 - Google Patents
脂化咪唑并喹啉衍生物 Download PDFInfo
- Publication number
- CN102264394B CN102264394B CN200980153132.5A CN200980153132A CN102264394B CN 102264394 B CN102264394 B CN 102264394B CN 200980153132 A CN200980153132 A CN 200980153132A CN 102264394 B CN102264394 B CN 102264394B
- Authority
- CN
- China
- Prior art keywords
- cell
- mpl
- tlr7
- compound
- core
- 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.)
- Expired - Fee Related
Links
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims description 3
- 102000004127 Cytokines Human genes 0.000 abstract description 21
- 108090000695 Cytokines Proteins 0.000 abstract description 21
- 229960005486 vaccine Drugs 0.000 abstract description 12
- 239000002671 adjuvant Substances 0.000 abstract description 10
- 239000000427 antigen Substances 0.000 abstract description 10
- 108091007433 antigens Proteins 0.000 abstract description 10
- 102000036639 antigens Human genes 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 230000003308 immunostimulating effect Effects 0.000 abstract description 5
- 239000000411 inducer Substances 0.000 abstract 2
- SQQXRXKYTKFFSM-UHFFFAOYSA-N chembl1992147 Chemical compound OC1=C(OC)C(OC)=CC=C1C1=C(C)C(C(O)=O)=NC(C=2N=C3C4=NC(C)(C)N=C4C(OC)=C(O)C3=CC=2)=C1N SQQXRXKYTKFFSM-UHFFFAOYSA-N 0.000 abstract 1
- 229940124669 imidazoquinoline Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 32
- 239000011162 core material Substances 0.000 description 23
- 238000009472 formulation Methods 0.000 description 21
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 20
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 20
- 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 18
- -1 amino, sulfydryl Chemical group 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
- 102400001093 PAK-2p27 Human genes 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 9
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 230000004913 activation Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 210000004443 dendritic cell Anatomy 0.000 description 7
- 230000036039 immunity Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 description 5
- 241001597008 Nomeidae Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 229950010550 resiquimod Drugs 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000012646 vaccine adjuvant Substances 0.000 description 4
- 229940124931 vaccine adjuvant Drugs 0.000 description 4
- MBEOKCONJLQHKT-UHFFFAOYSA-N 1-methylimidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(C)C=NC3=CN=C21 MBEOKCONJLQHKT-UHFFFAOYSA-N 0.000 description 3
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 3
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000024932 T cell mediated immunity Effects 0.000 description 3
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000005482 chemotactic factor Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000001163 endosome Anatomy 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 3
- ASAADZNSXOCOCZ-MXSWDONDSA-N (2s,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxyoxolane-2-carboxylic acid Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H]1O ASAADZNSXOCOCZ-MXSWDONDSA-N 0.000 description 2
- VVRQJMIECSNSCA-UHFFFAOYSA-N 4-imidazo[4,5-c]quinolin-1-ylbutan-1-ol Chemical compound C1=CC=CC2=C3N(CCCCO)C=NC3=CN=C21 VVRQJMIECSNSCA-UHFFFAOYSA-N 0.000 description 2
- FCZOVUJWOBSMSS-UHFFFAOYSA-N 5-[(6-aminopurin-9-yl)methyl]-5-methyl-3-methylideneoxolan-2-one Chemical compound C1=NC2=C(N)N=CN=C2N1CC1(C)CC(=C)C(=O)O1 FCZOVUJWOBSMSS-UHFFFAOYSA-N 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 102400001018 Proadrenomedullin N-20 terminal peptide Human genes 0.000 description 2
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000000139 costimulatory effect Effects 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
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000021633 leukocyte mediated immunity Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- PIRWNASAJNPKHT-SHZATDIYSA-N pamp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)N)C(C)C)C1=CC=CC=C1 PIRWNASAJNPKHT-SHZATDIYSA-N 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000011265 semifinished product Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- FBFJOZZTIXSPPR-UHFFFAOYSA-N 1-(4-aminobutyl)-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CCCCN)C3=C(N)N=C21 FBFJOZZTIXSPPR-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZWISCKSGNCMAQO-UHFFFAOYSA-N 3-nitro-1H-quinolin-4-one Chemical compound C1=CC=C2C(=O)C([N+](=O)[O-])=CNC2=C1 ZWISCKSGNCMAQO-UHFFFAOYSA-N 0.000 description 1
- TZFJPCFNVQSMAK-UHFFFAOYSA-N 4-(4-aminoimidazo[4,5-c]quinolin-1-yl)butan-1-ol Chemical compound NC1=NC2=CC=CC=C2C2=C1N=CN2CCCCO TZFJPCFNVQSMAK-UHFFFAOYSA-N 0.000 description 1
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical class NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- AYRAEZGFDYLZST-YPRCVSFVSA-N CCCCCCCCCCCCCCCC(OC[C@H](COP(O)(OCCN1c2c(cccc3)c3nc(N)c2NC1COCC)=O)OC(CCCCC/C=C/CCCCCCCC)=O)=O Chemical compound CCCCCCCCCCCCCCCC(OC[C@H](COP(O)(OCCN1c2c(cccc3)c3nc(N)c2NC1COCC)=O)OC(CCCCC/C=C/CCCCCCCC)=O)=O AYRAEZGFDYLZST-YPRCVSFVSA-N 0.000 description 1
- ZDGKUXICTQGZGK-UHFFFAOYSA-O CCOCc1nc2c([NH3+])nc(cccc3)c3c2[n]1CCCCO Chemical compound CCOCc1nc2c([NH3+])nc(cccc3)c3c2[n]1CCCCO ZDGKUXICTQGZGK-UHFFFAOYSA-O 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class 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 1
- 101000595548 Homo sapiens TIR domain-containing adapter molecule 1 Proteins 0.000 description 1
- 101000595554 Homo sapiens TIR domain-containing adapter molecule 2 Proteins 0.000 description 1
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 1
- 101000637726 Homo sapiens Toll/interleukin-1 receptor domain-containing adapter protein Proteins 0.000 description 1
- 101000649115 Homo sapiens Translocating chain-associated membrane protein 1 Proteins 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- HOOLXLAFPKUGPY-UHFFFAOYSA-N NC1=NC=2C(=CC=CC2C2=C1N=C(N2CCCCO)OCC)C.Cl Chemical compound NC1=NC=2C(=CC=CC2C2=C1N=C(N2CCCCO)OCC)C.Cl HOOLXLAFPKUGPY-UHFFFAOYSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- VXQUNLOWUAKALX-UHFFFAOYSA-N OCCCCC1=C(C(=NC2=CC=CC=C12)N)[N+](=O)[O-] Chemical compound OCCCCC1=C(C(=NC2=CC=CC=C12)N)[N+](=O)[O-] VXQUNLOWUAKALX-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 101100525628 Picea mariana SB62 gene Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 108010071811 Simian immunodeficiency virus Gag protein p27 Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100036073 TIR domain-containing adapter molecule 1 Human genes 0.000 description 1
- 229940124613 TLR 7/8 agonist Drugs 0.000 description 1
- 229940124614 TLR 8 agonist Drugs 0.000 description 1
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical compound CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 1
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 1
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 1
- 102100032120 Toll/interleukin-1 receptor domain-containing adapter protein Human genes 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102100027965 Translocating chain-associated membrane protein 1 Human genes 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- ZWELIJXAKMASLK-UGKPPGOTSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(=O)C)[C@@H](CO)O[C@H]1N1C(=O)SC2=CN=C(N)N=C21 ZWELIJXAKMASLK-UGKPPGOTSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000009621 actinic keratosis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 description 1
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- 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 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 150000004712 monophosphates Chemical class 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
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 108010062490 p27 antigen Proteins 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明化合物是佐剂分子,其包括共价连接磷脂基或膦脂基的咪唑并喹啉分子。本发明化合物已表明是干扰素-a、IL-12和其它免疫刺激细胞因子的诱导剂,且当用作疫苗抗原的佐剂时,与已知细胞因子诱导剂相比,具有提高的活性特征。
Description
背景
本发明涉及新的佐剂化合物、它们的制备方法、包含它们的组合物以及它们作为疫苗佐剂的用途。
微生物疫苗的精制和简化以及合成和重组亚基抗原用于提高疫苗的可制造性和安全导致疫苗效能的下降。这引起了对佐剂与抗原共同给药以提高疫苗活性以及合成和重组表位的弱免疫原性的研究。佐剂是增强针对疫苗抗原的体液和/或细胞介导免疫应答的添加物。但是,由于免疫***功能所涉及分子机制的复杂性质,疫苗佐剂的设计历史上是困难的。虽然长久以来已知添加微生物组分以增强适应性免疫应答,但是最近才表明,免疫监视所涉及细胞(例如上皮细胞和树突细胞)上的Toll样受体(TLR)通过所谓“病原相关模式”或“PAMP”结合许多的这些微生物产品。许多疫苗佐剂和独立的免疫调节剂似乎与TLR家族成员相互作用。
已鉴定的10种已知人TLR中,5种与细菌组分识别有关(TLR1、2、4、5、6),4种其它的(TLR3、7、8、9)似乎被限制在胞质小室中并与病毒RNA(TLR3、7、8)和去甲基化DNA(TLR9)的检测有关(Iwasaki,A.,Nat Immunol 2004,5,987)。TLR的活化调节胞内信号转导途径,并通过与胞内衔接物分子如MyD88、TRIF、TIRAP和TRAM的相互作用引起基因表达(Akira,S.Nat Rev Immunol 2004,4,499;Takeda,K.Semin Immunol 2004,16,3)。这些衔接物分子可有差别地调节炎症细胞因子/趋化因子和I型干扰素(IFNa/b)(可引起优先增强抗原特异性体液和细胞介导免疫应答)的表达(Zughaier,S.InfectImmun 2005,73,2940)。体液免疫是防御细菌病原体的主线,但是在病毒疾病和癌症情况下,细胞毒性T淋巴细胞(CTL)的诱导似乎对保护性免疫是决定性的。
目前,一组称为明矾的铝盐是人疫苗所用的主要佐剂。但是明矾通常只增强体液(Th2)免疫,并由于通过其它途径(例如皮下或皮内接种引起肉芽肿)的局部毒性而一般肌内使用(Aguilar,J.Vaccine 2007,25,3752)。明矾的其它潜在副作用包括增加IgE产生、变应原性和神经毒性。因此,需要新的安全有效的疫苗佐剂,其能够刺激抗体和Tb1型免疫应答,并与不同给药途径和抗原制剂兼容。
在TLR7和TLR8活化的情况下,必须识别天然(富含U和/或G)病毒ssRNA配体的几个不同类小分子模拟物。它们包括主要与TLR7相互作用的一些与氧化鸟苷代谢物(氧代鸟苷)相关的抗病毒化合物(Heil,F.Eur J Immunol 2003,33,2987;Hemmi,2002),以及结合TLR7和/或TLR8的腺嘌呤衍生物。这些化合物的免疫刺激能力归因于TLR/MyD88依赖性信号转导途径和细胞因子(包括IL-6以及I型(尤其干扰素-a)和II型干扰素)的产生。TLR7或TLR8活化引起上调树突细胞(DC)上的共刺激分子(例如CD-40、CD-80、CD-86)以及I类和II类MHC分子。DC是涉及T淋巴细胞吸收和提呈抗原的免疫***的主要细胞。浆细胞样树突细胞(plasmacytoid dendritic cell,pDC)优先表达TLR7,是专职的干扰素-a生产细胞;而mDC仅表达TLR8。mDC上的TLR8活化引起优先产生促炎细胞因子如IL-12、TNF-a和IFN-g以及细胞介导免疫(CMI)。
已受到相当关注的一类腺嘌呤衍生物是1H-咪唑并[4,5-c]喹啉(IQ)。当以乳膏形式局部施用时,发现该类咪喹莫德(imiquimod)(R847,S-26398)的原型成员有效对抗生殖***瘤病毒感染、光化性角化病和基底细胞癌。但是,咪喹莫德具有相当低的干扰素诱导活性,且口服和局部制剂均不无副作用。事实上,在利用咪喹莫德的HCV临床试验中报道了严重的副作用。TLR7激动剂的大部分免疫“足迹”通常已引起对毒性的关注:由于毒性问题最近暂停了利用另一TLR7激动剂ANA-975(氧代鸟苷衍生物)的临床试验。
瑞喹莫德(resiquimod)是IQ类TLR7/8配体的另一成员和咪喹莫德代谢物的衍生物。瑞喹莫德(R-848,S-28609)还以MyD88依赖性方式直接或间接地通过辅助分子活化巨噬细胞和DC中的TLR7,并上调DC中的共刺激分子和MHC I/II。与咪喹莫德相比,更具效能和毒性的瑞喹莫德还是TLR8信号转导的配体,其引起CD4+调节(Treg)细胞功能的逆转。最近利用转染HEK293细胞显示,TLR7激动剂在产生IFN-a和IFN调节细胞因子方面更有效,而TLR8激动剂在诱导促炎细胞因子如TNF-a和IL-12方面更有效,表明TLR7活化可能对抗体应答(Th2型应答)更为重要,而TLR8活化应促进CMI或Th1型免疫应答。然而如上所述,许多TLR7/8激动剂经常表现毒性、不稳定和/或具有非实质性免疫刺激作用。因此,发现和开发有效且安全的活化TLR7和/或TLR8的佐剂对通过帮助控制针对抗原的免疫应答大小、方向和持续时间来提高现有疫苗和新疫苗的功效和安全性是必要的。
与识别细胞表面上的PAMP的TLR2和LTR4不同,TLR7/8PAMP在内体/溶酶体小室中被感知,并需要内体成熟。在天然和异生素(zenobiotic)TLR7/8配体如咪喹莫德和瑞喹莫德情况下,细胞吸收是细胞活化的先决条件。因此,提高TLR7/8配体穿透DC和其它免疫细胞的策略可增强TLR活化和疫苗功效以及改善毒性作用。
核苷药物的脂缀合物是本领域已知一般用以增强口服生物利用度,以及允许将获得的“核苷脂(nucleolipid)”结合到脂质体的脂膜中。将不稳定和/或毒性药物结合到脂质体中建立了缓释载体***或分子贮库制剂,其保护药物免受降解并降低毒副作用。已报道这种“脂前药”的效能可比得上非衍生药物(US 5,827,831-NeXstar)。本领域已报道咪唑并喹啉和脂酰化IQ的贮库制剂用于在局部组织区域中维持IQ延长的时间以降低代谢和毒性之目的(WO 2005/001022-3M)。但是,当单独给药或与抗原一起以贮库制剂给药时,以特异方式将咪唑并喹啉与磷脂或膦脂缀合以促进到免疫细胞内的吸收,并增强内体TLR7/8活化和抗原呈递是本领域未知的。利用本发明化合物的增强免疫应答可能是因为式(I)化合物与内体TLR7和/或TLR8直接相互作用和/或在酶作用后活性代谢物的相互作用。
发明简述
本发明化合物已表明是干扰素-a、IL-12和其它免疫刺激细胞因子的诱导剂,且当用作治疗性或预防性治疗感染性疾病和癌症中的疫苗抗原的佐剂时,与已知细胞因子诱导剂相比,其可具有提高的活性-毒性特征。这些化合物本身也是新颖的。
附图说明
图1显示研究设计的示意图。
图2显示p27特异性CD8应答。
图3显示体内检测的p27特异性细胞毒活性。
图4阐述抗原特异性CD4T细胞应答。
图5显示用不含(-)或含不同量TLR7/8配体以及QS21和MPL的脂质体基制剂免疫的组中的血清细胞因子应答。
图6显示用不含(-)或含不同量TLR7/8配体以及QS21和MPL的乳剂基制剂免疫的组中的血清细胞因子应答。
发明概述
本发明化合物是佐剂分子,其包括可共价连接磷脂基或膦脂基的咪唑并喹啉分子。本发明化合物由式I或其药学上可接受的盐概括描述:
其中
R1=H、支链或直链且任选地末端用羟基、氨基、巯基、肼基、酰肼基、叠氮基、乙炔基、羧基或马来酰亚胺基(maleimido)取代的C1-6烷基、C1-6烷基氨基、C1-6烷氧基、C3-6环烷基C1-6烷基、C3-6环烷基C1-6烷基氨基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷基氨基、C1-6烷氧基C1-6烷氧基,
Z=未取代或末端由-(O-C2-C6烷基)1-6-取代的C2-C6烷基或烯基,
Y=O、NH
X=O、CH2、CF2
W=O或S
m=1-2,
其中
R2=H或直链/支链/不饱和C4-C24烷基或酰基
R3=直链/支链/不饱和C4-C24烷基或酰基
R4、R5=独立地为H、C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基;或者一起结合形成未取代或由一个或多个C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基取代的六员芳基、含一个氮原子的杂芳基、环烷基或含一个氮原子的杂环烷基。
在一个实施方案中,本发明化合物更具体地由式II描述:
其中
R1=H、支链或直链且任选地末端用羟基、氨基、巯基、肼基、酰肼基、叠氮基、乙炔基、羧基或马来酰亚胺基取代的C1-6烷基、C1-6烷基氨基、C1-6烷氧基、C3-6环烷基C1-6烷基、C3-6环烷基C1-6烷基氨基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷氧基C1-6烷基氨基、C1-6烷氧基C1-6烷氧基,
n=1-6
Y=O、NH
X=O、CH2、CF2
W=O或S
m=1-2
R2=H或直链/支链/不饱和C4-C24烷基或酰基
R3=直链/支链/不饱和C4-C24烷基或酰基(例如当W=O、X=O、m=1时,为磷脂酰基醚或酯、溶血磷脂酰基醚或酯)
表1
实施例 | 引用号 | R1 | n | m |
1 | - | - | - | - |
2 | - | - | - | - |
3 | L1 | H | 2 | 1 |
4 | L2 | n-Bu | 2 | 1 |
5 | L3 | CH2OEt | 2 | 1 |
6 | L4 | CH2OEt | 4 | 1 |
7 | - | - | - | - |
8 | L5 | CH2OEt | 2 | 2 |
9 | - | - | - | - |
对于所有示出实施例:Y=W=X=O;R2=R3=十六酰
实施例1
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-磷酰)烷基]-1H-咪唑并[4,5-c]喹啉(化合物(I),Y=W=X=O,m=1)的一般步骤:
依据下述本领域已知方法(Crossman,等.J ChemSoc,Perkin Trans1,1997,2769;Westerduin,等.Tet Lett,1986,15,6271;Nikolaev,等,Carbohydr Res,1990,204,65)通过偶联4-氨基-1-羟烷基-咪唑并喹啉III(Gerster等.J Med Chem 2005,48,3481;Izumi等.Bioorg Med Chem2003,11,2541)和1-H膦酸酯IV来制备咪唑并喹啉单磷酸甘油二酯V:将咪唑并喹啉III(1当量)和H-膦酸酯IV(2当量)悬浮到正庚烷中,并在蒸发溶剂之后在高真空下干燥过夜。将所得残余物溶于吡啶(0.01M化合物III),用新戊酰氯(12.4当量)处理,然后室温搅拌6小时。加入碘(4当量)的19∶1吡啶-水溶液(0.04M),室温搅拌所得混合物1小时,然后在CHCl3和1M Na2S2O5水溶液之间分配。将层分离,并用CHCl3萃取水层两次。用1M硼酸三乙铵缓冲液(pH 8)洗涤合并的有机萃取物,干燥(Na2SO4)并浓缩。通过硅胶快速色谱(梯度洗脱,0→25%MeOH-CHCl3)纯化所得残余物,再通过反相色谱(含1%TEA的CH3CN中的Bakerbond C8,用0→60%含1%Et3N的MeOH-CH3CN洗脱)得到无色固体化合物V。
实施例2
制备盐酸4-氨基-1-(4-羟丁基)-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉(化合物(III),R1=CH2OCH2CH3,n=4)
(1)在50℃用POCl3(1.2当量)逐滴处理并搅拌4-羟基-3-硝基喹啉(Gerster等.J Med Chem 2005,48,3481)的DMF悬浮液(0.7M)30分钟。将反应混合物倒入冰水,并用CH2Cl2萃取两次。用水洗涤合并的有机层,干燥(Na2SO4)并浓缩。将所得粗制品加到4-氨基-丁醇(1.3当量)和三乙胺(1.9当量)的EtOH溶液,并加热回流15分钟。浓缩后,硅胶快速色谱产出收率97%的黄色固体4-(4-羟丁基)氨基-3-硝基喹啉。
(2)将上面(1)所制化合物的EtOAc溶液(0.1M)在5%Pt/C(5%w/w)和MgSO4(1.5当量)存在下于50psig氢化6小时。将反应混合物过滤通过硅澡土并浓缩。将所得橙色油体与乙氧基乙酸(11当量)一起于150℃加热1小时。冷却反应混合物至0℃,用浓缩NH4OH碱化至pH 10,并用CH2Cl2萃取两次。干燥(Na2SO4)合并的有机层并浓缩。硅胶快速色谱(1∶60MeOH-CHCl3)产出乙氧基乙酸酯衍生物,用2.6M NaOH(5.0当量)的EtOH溶液(0.20M)室温处理1小时。减压除去乙醇,用AcOEt和CH2Cl2萃取水层数次。干燥(Na2SO4)合并的有机层并浓缩。硅胶快速色谱(梯度洗脱,1∶50→1∶15MeOH-CHCl3)产出收率74%的固体1-(4-羟丁基)-1H-咪唑并[4,5-c]喹啉。1H NMR(CDCl3,400MHz)δ9.29(s,1H),8.25(dd,2H),7.67(m,2H),4.89(s,2H),4.71(t,2H),3.79(m,2H),3.62(dd,2H),2.12(m,2H),1.82(m,2H),1.25(t,3H)。
(3)将上面(2)所制化合物和过乙酸(1.2当量)的乙醇溶液(0.4M)在60℃加热2.5小时。浓缩后,通过硅胶色谱(梯度洗脱,1∶30→1∶6MeOH-CHCl3)纯化得到的粗制品,以产出收率94%的黄色固体1-(4-羟丁基)-1H-咪唑并[4,5-c]喹啉5-N-氧化物。
(4)用NH4OH(30%水溶液,2,7mL)处理上面(3)所制化合物的CH2Cl2悬浮液(0.43M),之后滴加对甲苯磺酰氯(1.0当量)。室温搅拌所得混合物1.5小时并浓缩。硅胶快速色谱(梯度洗脱,1∶30→1∶9MeOH-CHCl3)产出定量产率的橙色固体4-氨基-1-(4-羟丁基)-1H-咪唑并[4,5-c]喹啉。
(5)在50℃滴加4N HCl的二烷溶液处理上面(4)所制化合物的二烷溶液(0.12M),之后使其冷却至室温。收集固体沉淀,用二烷洗涤,干燥产出收率89%的盐酸4-氨基-1-(4-羟丁基)-1H-咪唑并[4,5-c]喹啉:1H NMR(CDCl3-CD3OD,400MHz)δ8.13(d,1H),7.97(d,1H),7.65(t,1H),7.55(t,1H),4.89(bs,2H),4.68(m,2H),3.75(m,2H),3.68(dd,2H),2.10(m,2H),1.80(m,2H),1.29(t,3H)。13C NMR(CDCl3-CD3OD,100MHz)δ151.9,148.1,135.8,133.7,130.2,128.7,125.8,125.4,122.5,121.2,118.8,112.1,66.8,64.0,60.8,46.8,28.6,26.6,14.5。HRMS[M+H]+计算值315.1821,实测值315.1839。
实施例3(L1)
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-磷酰)乙基]-1H-咪唑并[4,5-c]喹啉(化合物(I),R1=H,Y=W=X=O,n=2,m=1,R2=R3=n-C15H31CO)
按照上面实施例1所述一般步骤以收率80%制备化合物L1:1HNMR(CDCl3-CD3OD,400MHz)δ8.22(s,1H),8.16(d,1H),7.41(t,1H),7.21(t,1H),6.92(d,1H),5.26(m,1H),4.82(bs,2H),4.67(bs,2H),4.42(dd,1H),4.20(dd,1H),4.05(t,2H),3.14(q,1H),2.31(m,4H),1.59(m,4H),1.25(m,48H),0.88(m,6H);13C NMR(CDCl3-CD3OD,100MHz):δ173.6,173.2,148.1,145.8,134.5,133.9,129.3,125.5,124.5,118.4,112.3,100.3,77.2,70.1,70.0,63.5,62.3,45.9,34.1,33.9,31.7,29.5,29.5,29.3,29.2,29.1,29.1,28.9,28.9,24.7,24.7,22.5,13.9,8.3。HRMS[M+H]+计算值859.5714,实测值859.5688。
实施例4(L2)
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-磷酰)乙基]-2-丁基-1H-咪唑并[4,5-c]喹啉(化合物(I),R1=n-C4H9,Y=W=X=O,n=2,m=1,R2=R3=n-C15H31CO)
按照上面实施例1所述一般步骤以收率78%制备化合物L2:1HNMR(CDCl3-CD3OD,400MHz):δ8.23(bs,1H),7.39(t,1H),7.22(bs,1H),6.93(bs,1H),5.25(m,1H),4.7(bs,2H),4.6(bs,2H),4.42(dd,1H),4.19(dd,1H),4.04(t,2H),3.06(bs,2H)2.32(m,4H),1.96(p,2H)1.59(m,6H)1.26(m,48H),1.07(t,3H),0.88(m,6H);13C NMR(CDCl3-CD3OD,100MHz):δ173.6,173.2,157.2,147.4,135.2,133.6,128.8,124.2,123.6,120.9,118.2,112.2,77.2,70.0,69.9,63.2,62.2,46.3,33.9,33.7,31.6,29.3,29.3,29.3,29.1,29.0,28.95,28.9,28.8,28.7,28.6,27.0,24.5,24.5,22.3,22.1,13.6,13.4。HRMS:[M+H]+计算值915.6340,实测值915.6309。
实施例5(L3)
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-磷酰)乙基]-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉(化合物(I),R1=CH2OCH2CH3,Y=W=X=O,n=2,m=1,R2=R3=n-C15H31CO)
按照上面实施例1所述一般步骤以收率86%制备化合物L3:1HNMR(CDCl3-CD3OD,400MHz):δ8.05(bs,1H),7.29(t,1H),7.09(bs,1H),6.78(bs,1H),5.11(m,1H),4.80(bs,4H),4.60(bs,2H),4.28(dd,1H),4.07(dd,1H),3.90(t,2H),3.54(q,2H)2.18(m,4H),1.59(m,4H)1.16(m,51H),0.76(m,6H);13C NMR(CDCl3-CD3OD,100MHz):δ173.4,173.0,153.3,148.2,135.7,134.7,129.1,124.4,124.2,121.1,119.1,112.8,77.2,70.2,66.6,65.4,63.5,62.5,57.7,47.1,45.7,34.3,34.1,31.9,29.7,29.7,29.6,29.5,29.3,29.3,29.1,29.1,24.9,22.7,15.0,14.1,8.6。HRMS:[M+H]+计算值915.6340,实测值915.6309。
实施例6(L4)
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-磷酰)丁基]-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉(化合物(I),R1=H,Y=W=X=O,n=4,m=1,R2=R3=n-C15H31CO)
按照上面实施例1所述一般步骤以收率26%制备化合物L4:1HNMR(CDCl3,400MHz):δ11.2(bs,1H),7.78(d,1H),7.30(t,1H),7.20(d,1H),6.78(t,1H),6.39(bs,1H),5.28(m,1H),4.79(s,2H),4.43-4.50(m,3H),4.11-4.27(m,5H),3.67(dd,2H),2.41(bs,2H),2.30(dd,4H),1.96(bs,1H),1.60(m,4H),1.25(m,54H),0.88(1,6H);13C NMR(CDCl3,100MHz):δ173.4,173.0,150.9,148.9,134.7,134.2,128.0,124.3(2),120.5,118.4,111.8,70.3,70.2,66.8,64.7,64.4,64.3,63.4(2),62.4,46.6,34.2,34.1,31.9,29.6(3),29.4,29.3(2),29.2,29.1,28.2,27.4,24.8(2),22.6,15.1,14.1。HRMS[M-H]-计算值943.6289,实测值943.6251。
实施例7
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油基-3-二磷酰)烷基]-1H-咪唑并[4,5-c]喹啉(化合物(I),Y=W=X=O,m=2)的一般步骤
依据下述本领域已知方法(Biochim.Biophys.Acta 1980,619,604,J.Biol.Chem.,1990,265(11),(6112-6117)J. Org.Chem.1997,62,2144-2147)通过偶联咪唑并喹啉单磷酸吗啉酯VI(由咪唑并喹啉III制备的粗制形式)和1,2-二酰基-sn-甘油-3-磷酸酯钠盐VII来制备咪唑并喹啉二磷酸甘油二酯VIII:在0℃将POCl3(2.0当量)和咪唑并喹啉III(1.0当量)加入磷酸三甲基酯(0.38M)。在0℃搅拌15小时后,在H2O和Et2O之间分配反应混合物并分离各层。用H2O萃取有机层3次,并用NH4OH水溶液调节合并水层的pH至pH 9。浓缩水溶液,高真空下干燥,并通过利用CHCl3-MeOH-H2O-Et3N(梯度洗脱,90∶10∶0.5∶0.5→60∶40∶5∶1)的硅胶色谱纯化所得残余物。将所得产物在50℃溶于二烷(0.12M),并用4N HCl(1.5当量)处理。收集沉淀的HCl盐,用二烷冲洗,并高真空下干燥。将吗啉(5.0当量)加入该盐的1∶1t-BuOH-H2O(0.5M)悬浮液中,加热反应混合物至90℃,并用1,3-二环己基碳二亚胺的t-BuOH溶液(0.33M)处理。在90℃维持1小时后,在H2O和Et2O之间分配冷却的反应混合物,并分离各层。用H2O萃取有机层两次,浓缩合并的水层并高真空下干燥。真空浓缩所得粗磷酸吗啉酯VI(1.5当量)和VII(1.0当量)的小体积吡啶悬浮液,然后用甲苯共蒸发两次,并高真空下干燥;再重复该步骤两次。然后将4,5-二氰基咪唑(DCI,3.0当量)加入干燥固体的吡啶悬浮液(0.10M)中,室温搅拌反应混合物10天。浓缩得到的混合物,在H2O-CH2Cl2之间分配所得残余物,并分离各层。用CH2Cl2萃取水层两次,干燥(Na2SO4)并浓缩合并的有机层。利用CHCl3-MeOH-H2O(梯度洗脱,90∶10∶0.5→70∶30∶2)的硅胶色谱产出无色固体化合物VIII。
实施例8(L5)
制备4-氨基-1-[2-(1,2-二软脂酰-sn-甘油-3-二磷酰)乙基]-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉(化合物(I),R1=CH2OCH2CH3,Y=W=X=O,n=2,m=2,R2=R3=n-C15H31CO)
按照上面实施例6所述一般步骤以收率22%制备化合物L5:1HNMR(CDCl3,400MHz):δ8.17(bs,1H),7.10-7.40(2-3m,2-3H),5.25(bs,1H),4.60-5.00(bm,3H),4.38(m,1H),4.05-4.22(m,3H),3.60-3.82(m,4H),3.41(bs,1H),3.10(dd,Et3N的2H),2.28(m,4H),1.84(dd,1H),1.56(m,5H),1.25(m,54H),0.88(t,7H);13C NMR(CDCl3,100MHz):δ173.5,173.1,152.4,147.7,135.8,134.2,128.8,124.5,123.6,122.0,118.8,112.2,77.2,70.0,68.1,66.5,63.8,62.4,54.6,46.5,45.5,38.5,33.9,33.0,29.5,29.4,29.1,28.9,28.7,25.0,24.6,23.5,22.7,22.5,14.6,13.8,13.7,13.2,10.7,8.1。HRMS[M+H]+计算值997.5796,实测值997.5776。
实施例9
脂化TLR7/8的体内试验
TLR7/8配体可促进小鼠多个方面的免疫应答,引人注意的是CD8应答。利用例如下述技术研究TLR7/8配体(“核心”化合物)和其对应脂化衍生物之间的应答差异。
用于比较研究的化合物制剂需要考虑核心和脂化分子间的不同分子量(例如45和4.5μg脂化化合物L3对应约15和1.5μg对应核心化合物“L3核心”),以便能够在研究中并列比较对应基团。还测试了较高剂量的L3(200μg)和L3核心(150μg)。在一个这样的研究中,下面概括和描述的制剂用于接种6-8周龄C57BL/6(H2Kb)雌小鼠(10只/组)。小鼠接受间隔14天的两次注射,并在第1、3和4周抽血(精确抽血日见图1)。肌内接种小鼠。利用编码SIV-p27蛋白的重组腺病毒和加佐剂的p27的相异的初次免疫/加强免疫用作对照组,腺病毒注射剂量为5x 108VP。研究设计示于图1。
说明 | p27 | QS21 | MPL | SB62cb | L3 | L3核心 |
QS/MPL(脂质体基制剂) | 5 | 5 | 5 | - | - | - |
QS/MPL+200μg L3 | 5 | 5 | 5 | - | 200 | - |
QS/MPL+45μg L3 | 5 | 5 | 5 | - | 45 | - |
QS/MPL+4.5μg L3 | 5 | 5 | 5 | - | 4.5 | - |
QS/MPL+150μg L3核心 | 5 | 5 | 5 | - | - | 150 |
QS/MPL+15μg L3核心 | 5 | 5 | 5 | - | - | 15 |
QS/MPL+1.5μg L3核心 | 5 | 5 | 5 | - | - | 1.5 |
QS/MPL/SB62C(乳剂基制剂) | 5 | 5 | - | 5μl | - | - |
QS/MPL/SB62C+200μg L3 | 5 | 5 | 5 | 5μl | 200 | - |
QS/MPL/SB62C+45μg L3 | 5 | 5 | 5 | 5μl | 45 | - |
QS/MPL/SB62C+4.5μg L3 | 5 | 5 | 5 | 5μl | 4.5 | - |
QS/MPL/SB62C+150μg L3核心 | 5 | 5 | 5 | 5μl | - | 150 |
QS/MPL/SB62C+15μg L3核心 | 5 | 5 | 5 | 5μl | - | 15 |
QS/MPL/SB62C+1.5μg L3核心 | 5 | 5 | 5 | 5μl | - | 1.5 |
p27 | 5 | - | - | - | - | - |
未用药的 | - | - | - | - | - | - |
表1:制剂概述
除非另外指明,所有化合物以μg计。
bSB62c包含水包油SB62和胆固醇
在研究设计中,将分子配制成含QS21和MPL免疫刺激剂的脂质体基或水包油基佐剂组合物。为评估TLR7/8L的加入值,将由包含TLR7/8L、QS21和MPL的制剂诱导的先天和适应性免疫应答与由对应的包含QS21和MPL的制剂诱导的比较。
通过在第二次注射后7天测量胞内细胞因子来评估抗原特异性CD8和CD4应答的诱导。在包括整个p27抗原(15-聚体肽,重叠11)的多种肽的合并物存在下刺激外周血淋巴细胞(PBL)。通过布雷菲尔德菌素A阻断细胞因子的分泌,并在用合适抗体胞内染色之后,通过流式细胞术评估3种细胞因子(IFNγ、TNFα和IL2)的存在情况。
利用CRX-642及其脂化物L3进行与上述类似的研究。图2和3显示第二次免疫后7天观察的p27特异性T细胞频度。与无TLR7/8L的对照制剂相比,当含L3的脂质体与MPL和QS-21制剂共同给药时,明显以剂量依赖方式增加了p27特异性CD8频度(图2)。引人注意的是,与对应的无TLR7/8L的对照制剂相比,在脂化TLR7/8L存在下,脂质体基制剂和水包油基制剂均得以提高CD8应答。而且,生成产细胞因子CD8T细胞的能力取决于TLR7/8配体的脂化性质,因为核心分子L3核心相比L3未提高应答。
作为对评估诱导的CD8应答的补充,还可体内评估抗原特异性胞毒活性。简言之,将跨整个蛋白的p27肽的脉冲靶标和对照未脉冲靶标注射到免疫小鼠中,并在注射后24小时,通过脉冲靶标的消失评估p27特异性胞毒性。
与上面说明的L3核心和L3的诱导CD8应答的评估一起进行补体胞毒活性(complementary cytotoxic activity)研究。与接受核心TLR7/8配体基制剂的小鼠相比,在用脂化TLR7/8配体基制剂免疫的小鼠中检测到更高的胞毒活性(图3)。该活性比由仅基于QS21和MPL的对照制剂诱导的活性高,特别是在使用高剂量脂化TLR7/8L时。
如对于CD8应答所示,当含L3的脂质体与含MPL和QS-21的脂质体基制剂一起给药时,与对照制剂相比,p27特异性CD4频度增加(图4)。对于CD8应答,核心分子L3核心不能够诱导超过由对照制剂诱导的CD4应答。
当以乳剂基制剂给药时,脂化TLR7/8L也能够提高CD4T细胞应答超过由对照制剂达到的水平。
当被脂化时,不同制剂中TLR7/8配体的增加值通过产细胞因子T细胞频度5倍的增加来表示(CD8和CD4T细胞二者)。令人关注的是,T细胞应答的细胞因子特征由高频度双阳性T细胞(IFNγ+TNFα+)表征。
另外的研究阐述了脂化TLR7/8化合物诱导内源趋化因子和促炎细胞因子的能力,其中已知I型IFN为稚CD8T细胞的程序(存活、分化和记忆发育)所需要。在第一次注射3和24小时后,在小鼠血清中测量这些细胞因子(图5和6)。
L3核心和L3的细胞因子特征结果显示在脂质体基和乳剂基制剂之间观察到类似的细胞因子特征。已知TLR7/8配体因它们刺激浆细胞样树突细胞的能力诱导IFNα,且确实在用L3免疫小鼠中以剂量依赖方式检测到IFNα,与其核心物L3核心相比处于较高水平。也检测到接近本底水平的低IL-12p70产生。在低剂量L3时INFγ水平增加,而当L3核心和L3均加入QS21和MPL中时,其它炎症细胞因子如TNFα或IL-6提高。对于两种化合物,趋化因子MCP-1和MIG均增加至10倍。总之,这些数据表明,与对应的核心分子相比,受试脂化分子在体内诱导细胞因子产生方面即使不更具效能也是等效的。
Claims (1)
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10821008P | 2008-10-24 | 2008-10-24 | |
US61/108210 | 2008-10-24 | ||
US22422609P | 2009-07-09 | 2009-07-09 | |
US61/224226 | 2009-07-09 | ||
US22993309P | 2009-07-30 | 2009-07-30 | |
US61/229933 | 2009-07-30 | ||
PCT/US2009/061867 WO2010048520A1 (en) | 2008-10-24 | 2009-10-23 | Lipidated imidazoquinoline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102264394A CN102264394A (zh) | 2011-11-30 |
CN102264394B true CN102264394B (zh) | 2014-01-01 |
Family
ID=42119702
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200980153132.5A Expired - Fee Related CN102264394B (zh) | 2008-10-24 | 2009-10-23 | 脂化咪唑并喹啉衍生物 |
Country Status (23)
Country | Link |
---|---|
US (2) | US8624029B2 (zh) |
EP (1) | EP2341933B1 (zh) |
JP (1) | JP5695569B2 (zh) |
KR (1) | KR20110077004A (zh) |
CN (1) | CN102264394B (zh) |
AU (1) | AU2009308278B2 (zh) |
BR (1) | BRPI0919937A2 (zh) |
CA (1) | CA2741291A1 (zh) |
CY (1) | CY1119981T1 (zh) |
DK (1) | DK2341933T3 (zh) |
ES (1) | ES2656813T3 (zh) |
HR (1) | HRP20180063T1 (zh) |
HU (1) | HUE036531T2 (zh) |
IL (1) | IL212417A (zh) |
LT (1) | LT2341933T (zh) |
MX (1) | MX2011004249A (zh) |
NO (1) | NO2341933T3 (zh) |
PL (1) | PL2341933T3 (zh) |
PT (1) | PT2341933T (zh) |
SI (1) | SI2341933T1 (zh) |
TR (1) | TR201802083T4 (zh) |
WO (1) | WO2010048520A1 (zh) |
ZA (1) | ZA201103590B (zh) |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102272134B (zh) | 2008-12-09 | 2013-10-16 | 吉里德科学公司 | Toll样受体调节剂 |
SI2491035T1 (sl) | 2009-10-22 | 2017-10-30 | Gilead Sciences, Inc. | Derivati purina ali deazapurina uporabni za zdravljenje (med drugimi) virusnih okužb |
GB201009273D0 (en) * | 2010-06-03 | 2010-07-21 | Glaxosmithkline Biolog Sa | Novel vaccine |
JP2013538217A (ja) * | 2010-09-01 | 2013-10-10 | ノバルティス アーゲー | 不溶性金属塩への免疫増強物質の吸着 |
US8728486B2 (en) | 2011-05-18 | 2014-05-20 | University Of Kansas | Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds |
GB201119999D0 (en) | 2011-11-20 | 2012-01-04 | Glaxosmithkline Biolog Sa | Vaccine |
GB201120000D0 (en) | 2011-11-20 | 2012-01-04 | Glaxosmithkline Biolog Sa | Vaccine |
EP2638896A1 (en) * | 2012-03-14 | 2013-09-18 | Bioneer A/S | Cationic liposomal drug delivery system for specific targeting of human cd14+ monocytes in whole blood |
EP2674170B1 (en) * | 2012-06-15 | 2014-11-19 | Invivogen | Novel compositions of TLR7 and/or TLR8 agonists conjugated to lipids |
EP2732825B1 (en) | 2012-11-19 | 2015-07-01 | Invivogen | Conjugates of a TLR7 and/or TLR8 agonist and a TLR2 agonist |
US20140242112A1 (en) * | 2012-11-30 | 2014-08-28 | Glaxosmithkline Biologicals S.A. | Novel vaccine |
EP2769738B1 (en) | 2013-02-22 | 2016-07-20 | Invivogen | Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists |
US9295732B2 (en) | 2013-02-22 | 2016-03-29 | Invivogen | Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists |
WO2015023958A1 (en) * | 2013-08-15 | 2015-02-19 | The University Of Kansas | Toll-like receptor agonists |
GB201321242D0 (en) | 2013-12-02 | 2014-01-15 | Immune Targeting Systems Its Ltd | Immunogenic compound |
EP3110401A4 (en) | 2014-02-25 | 2017-10-25 | Merck Sharp & Dohme Corp. | Lipid nanoparticle vaccine adjuvants and antigen delivery systems |
MX2017000026A (es) | 2014-07-11 | 2017-05-01 | Gilead Sciences Inc | Moduladores de receptores tipo toll para el tratamiento de virus de inmunodeficiencia humana (vih). |
MX2017003284A (es) | 2014-09-16 | 2017-06-28 | Gilead Sciences Inc | Formas solidas de modulador de receptor tipo toll. |
WO2016075661A1 (en) | 2014-11-13 | 2016-05-19 | Glaxosmithkline Biologicals Sa | Adenine derivatives which are useful in the treatment of allergic diseases or other inflammatory conditions |
WO2017021912A1 (en) | 2015-08-06 | 2017-02-09 | Glaxosmithkline Intellectual Property Development Limited | Combined tlrs modulators with anti ox40 antibodies |
US10597397B2 (en) | 2015-09-29 | 2020-03-24 | Sumitomo Dainippon Pharma Co., Ltd. | Adenine conjugate compounds and their use as vaccine adjuvants |
HUE064322T2 (hu) | 2015-10-07 | 2024-03-28 | Sumitomo Pharma Co Ltd | Pirimidin vegyületet és patogén eredetû antigént tartalmazó készítmény |
ES2831162T3 (es) | 2015-12-14 | 2021-06-07 | Glaxosmithkline Biologicals Sa | Fosfolipidación de imidazoquinolinas y oxoadeninas |
MX2018007319A (es) * | 2015-12-14 | 2018-09-06 | Glaxosmithkline Biologicals Sa | Imidazoquinolinas pegiladas como agonistas tlr7 y tlr8. |
US9966457B2 (en) | 2016-03-18 | 2018-05-08 | Globalfoundries Inc. | Transistor structure with varied gate cross-sectional area |
BE1024865B1 (fr) * | 2016-09-07 | 2018-07-31 | Glaxosmithkline Biologicals Sa | Derives d'imidazoquinoleine |
WO2018181420A1 (ja) | 2017-03-29 | 2018-10-04 | 大日本住友製薬株式会社 | ワクチンアジュバント製剤 |
CA3085424A1 (en) | 2017-12-21 | 2019-06-27 | Sumitomo Dainippon Pharma Co., Ltd. | Combination drug including tlr7 agonist |
KR20210034614A (ko) | 2018-07-23 | 2021-03-30 | 국립감염증연구소장이 대표하는 일본국 | 인플루엔자 백신을 포함하는 조성물 |
US20220241410A1 (en) | 2019-05-23 | 2022-08-04 | The University Of Montana | Vaccine adjuvants based on tlr receptor ligands |
CN112778372A (zh) * | 2019-11-11 | 2021-05-11 | 苏州泽璟生物制药股份有限公司 | 咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用 |
US20230373997A1 (en) * | 2020-10-08 | 2023-11-23 | Icahn School Of Medicine At Mount Sinai | Imdq-peg-chol adjuvant and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5663387A (en) * | 1994-03-30 | 1997-09-02 | The United States Of America As Represented By The Secretary Of The Navy | Liposomes containing polymerized lipids for non-covalent immobilization of proteins and enzymes |
CN101056877A (zh) * | 2004-09-14 | 2007-10-17 | 诺华疫苗和诊断公司 | 咪唑并喹啉化合物 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ285420B6 (cs) * | 1990-04-24 | 1999-08-11 | Ústav Organické Chemie A Biochemie Avčr | N-(3-Fluor-2-fosfonylmethoxypropyl)deriváty purinových a pyrimidinových heterocyklických bazí, způsoby jejich přípravy a použití |
JP2005519990A (ja) * | 2001-10-12 | 2005-07-07 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | イミダゾキノリン化合物を用いて免疫応答を増強するための方法および産物 |
EP2269632B1 (en) | 2002-08-15 | 2014-01-01 | 3M Innovative Properties Co. | Immunostimulatory compositions and methods of stimulating an immune response |
WO2005001022A2 (en) | 2003-04-10 | 2005-01-06 | 3M Innovative Properties Company | Methods and compositions for enhancing immune response |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
RU2412942C2 (ru) * | 2003-10-03 | 2011-02-27 | 3М Инновейтив Пропертиз Компани | Оксизамещенные имидазохинолины, способные модулировать биосинтез цитокинов |
EP1550458A1 (en) * | 2003-12-23 | 2005-07-06 | Vectron Therapeutics AG | Synergistic liposomal adjuvants |
US20060051374A1 (en) * | 2004-04-28 | 2006-03-09 | 3M Innovative Properties Company | Compositions and methods for mucosal vaccination |
US8907153B2 (en) * | 2004-06-07 | 2014-12-09 | Nuvo Research Inc. | Adhesive peel-forming formulations for dermal delivery of drugs and methods of using the same |
US7998945B2 (en) * | 2005-12-23 | 2011-08-16 | Jado Technologies Gmbh | Methods for the treatment and amelioration of atopic dermatitis |
-
2009
- 2009-10-23 LT LTEP09822779.6T patent/LT2341933T/lt unknown
- 2009-10-23 EP EP09822779.6A patent/EP2341933B1/en active Active
- 2009-10-23 AU AU2009308278A patent/AU2009308278B2/en not_active Ceased
- 2009-10-23 BR BRPI0919937A patent/BRPI0919937A2/pt not_active IP Right Cessation
- 2009-10-23 HU HUE09822779A patent/HUE036531T2/hu unknown
- 2009-10-23 KR KR1020117011672A patent/KR20110077004A/ko active IP Right Grant
- 2009-10-23 PT PT98227796T patent/PT2341933T/pt unknown
- 2009-10-23 CA CA2741291A patent/CA2741291A1/en not_active Abandoned
- 2009-10-23 NO NO09822779A patent/NO2341933T3/no unknown
- 2009-10-23 MX MX2011004249A patent/MX2011004249A/es active IP Right Grant
- 2009-10-23 PL PL09822779T patent/PL2341933T3/pl unknown
- 2009-10-23 CN CN200980153132.5A patent/CN102264394B/zh not_active Expired - Fee Related
- 2009-10-23 SI SI200931796T patent/SI2341933T1/en unknown
- 2009-10-23 ES ES09822779.6T patent/ES2656813T3/es active Active
- 2009-10-23 DK DK09822779.6T patent/DK2341933T3/da active
- 2009-10-23 WO PCT/US2009/061867 patent/WO2010048520A1/en active Application Filing
- 2009-10-23 JP JP2011533375A patent/JP5695569B2/ja not_active Expired - Fee Related
- 2009-10-23 US US13/125,342 patent/US8624029B2/en active Active
- 2009-10-23 TR TR2018/02083T patent/TR201802083T4/tr unknown
-
2011
- 2011-04-17 IL IL212417A patent/IL212417A/en active IP Right Grant
- 2011-05-16 ZA ZA2011/03590A patent/ZA201103590B/en unknown
-
2013
- 2013-12-20 US US14/135,900 patent/US8946421B2/en active Active
-
2018
- 2018-01-15 HR HRP20180063TT patent/HRP20180063T1/hr unknown
- 2018-01-23 CY CY20181100086T patent/CY1119981T1/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5663387A (en) * | 1994-03-30 | 1997-09-02 | The United States Of America As Represented By The Secretary Of The Navy | Liposomes containing polymerized lipids for non-covalent immobilization of proteins and enzymes |
CN101056877A (zh) * | 2004-09-14 | 2007-10-17 | 诺华疫苗和诊断公司 | 咪唑并喹啉化合物 |
Also Published As
Publication number | Publication date |
---|---|
ZA201103590B (en) | 2012-10-31 |
EP2341933B1 (en) | 2017-11-22 |
CA2741291A1 (en) | 2010-04-29 |
EP2341933A4 (en) | 2012-03-14 |
KR20110077004A (ko) | 2011-07-06 |
EP2341933A1 (en) | 2011-07-13 |
BRPI0919937A2 (pt) | 2016-02-16 |
MX2011004249A (es) | 2011-07-20 |
IL212417A (en) | 2017-01-31 |
CN102264394A (zh) | 2011-11-30 |
IL212417A0 (en) | 2011-06-30 |
HRP20180063T1 (hr) | 2018-02-23 |
SI2341933T1 (en) | 2018-03-30 |
PL2341933T3 (pl) | 2018-04-30 |
PT2341933T (pt) | 2018-02-13 |
AU2009308278B2 (en) | 2014-11-27 |
TR201802083T4 (tr) | 2018-03-21 |
CY1119981T1 (el) | 2018-12-12 |
DK2341933T3 (da) | 2018-01-29 |
US20140323731A1 (en) | 2014-10-30 |
HUE036531T2 (hu) | 2018-07-30 |
US8624029B2 (en) | 2014-01-07 |
JP5695569B2 (ja) | 2015-04-08 |
US20110282061A1 (en) | 2011-11-17 |
JP2012506865A (ja) | 2012-03-22 |
AU2009308278A1 (en) | 2010-04-29 |
ES2656813T3 (es) | 2018-02-28 |
US8946421B2 (en) | 2015-02-03 |
NO2341933T3 (zh) | 2018-04-21 |
LT2341933T (lt) | 2018-04-10 |
WO2010048520A1 (en) | 2010-04-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102264394B (zh) | 脂化咪唑并喹啉衍生物 | |
CN102469790B (zh) | 脂质化氧代腺嘌呤衍生物 | |
JP7104096B2 (ja) | 脂質付加された免疫反応調節化合物の組成物、製剤及び方法 | |
CN105188373B (zh) | 抑制“干扰素基因刺激蛋白”依赖性信号传导的组合物和方法 | |
JP6453855B2 (ja) | 「インターフェロン遺伝子の刺激因子」依存性シグナル伝達を活性化するための組成物及び方法 | |
US10988500B2 (en) | Lipid A mimics, methods of preparation, and uses thereof | |
CN108542913A (zh) | 包含具有确定立体化学的环嘌呤二核苷酸的组合物及其制备和使用方法 | |
Wang et al. | Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice | |
CN111601900A (zh) | 寡核苷酸构建体及其用途 | |
RU2479317C2 (ru) | Применение мономиколилглицерина (mmg) в качестве адъюванта | |
TW201412330A (zh) | 陽離子之脂質疫苗組合物及其使用方法 | |
EP2664345B1 (en) | Vaccine for inducing an improved immune reaction | |
Marshall et al. | Polymyxin B enhances ISS-mediated immune responses across multiple species | |
US20220257752A1 (en) | New use of cyclic dinucleotides | |
AU2018202168B2 (en) | Lipidated immune response modifier compound compositions, formulations, and methods | |
Tang et al. | Construction of an Immunostimulatory Plasmid, pUCpGs10, and Research on its Immune Adjuvant Effect | |
AU2015202390A1 (en) | Lipidated immune response modifier compound compositions, formulations, and methods |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140101 Termination date: 20201023 |