NZ714267B2 - Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases - Google Patents
Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases Download PDFInfo
- Publication number
- NZ714267B2 NZ714267B2 NZ714267A NZ71426714A NZ714267B2 NZ 714267 B2 NZ714267 B2 NZ 714267B2 NZ 714267 A NZ714267 A NZ 714267A NZ 71426714 A NZ71426714 A NZ 71426714A NZ 714267 B2 NZ714267 B2 NZ 714267B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- compound
- aryl
- carboxylic
- halogen
- Prior art date
Links
- KCTZOTUQSGYWLV-UHFFFAOYSA-N N1C=NC=C2N=CC=C21 Chemical class N1C=NC=C2N=CC=C21 KCTZOTUQSGYWLV-UHFFFAOYSA-N 0.000 title abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 6
- 201000010099 disease Diseases 0.000 title abstract description 4
- 208000036142 Viral infection Diseases 0.000 title description 5
- 230000009385 viral infection Effects 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000012453 solvate Substances 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 11
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 8
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 8
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229940124530 sulfonamide Drugs 0.000 claims description 7
- 150000003456 sulfonamides Chemical class 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 102000002689 Toll-like receptor Human genes 0.000 description 16
- 108020000411 Toll-like receptor Proteins 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 239000007787 solid Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- -1 dioxolinyl Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 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 4
- 239000003643 water by type Substances 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000411 inducer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- QJIMTLTYXBDJFC-UHFFFAOYSA-N (4-methylphenyl)-diphenylphosphane Chemical compound C1=CC(C)=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJIMTLTYXBDJFC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- AZLCYKXTUNHMLH-UHFFFAOYSA-N methyl N-(4-oxo-3,5-dihydropyrrolo[3,2-d]pyrimidin-2-yl)carbamate Chemical compound COC(=O)Nc1nc(O)c2[nH]ccc2n1 AZLCYKXTUNHMLH-UHFFFAOYSA-N 0.000 description 2
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- WNGBGXLNOIQJGE-UHFFFAOYSA-N (4-methyl-1,2-oxazol-3-yl)methanol Chemical compound CC1=CON=C1CO WNGBGXLNOIQJGE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PAELIJAKXXNAMC-UHFFFAOYSA-N COC(=O)CNC(=S)NCC(=O)OC Chemical compound COC(=O)CNC(=S)NCC(=O)OC PAELIJAKXXNAMC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 101100166531 Drosophila melanogaster CycC gene Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 101000852870 Homo sapiens Interferon alpha/beta receptor 1 Proteins 0.000 description 1
- 101000763579 Homo sapiens Toll-like receptor 1 Proteins 0.000 description 1
- 101000763537 Homo sapiens Toll-like receptor 10 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 102100036714 Interferon alpha/beta receptor 1 Human genes 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
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 101100481581 Mus musculus Tlr13 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229940124613 TLR 7/8 agonist Drugs 0.000 description 1
- 241001441723 Takifugu Species 0.000 description 1
- 102100027010 Toll-like receptor 1 Human genes 0.000 description 1
- 102100027009 Toll-like receptor 10 Human genes 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- XWRLQRLQUKZEEU-UHFFFAOYSA-N ethyl(hydroxy)silicon Chemical class CC[Si]O XWRLQRLQUKZEEU-UHFFFAOYSA-N 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 102000045715 human TLR7 Human genes 0.000 description 1
- 102000045720 human TLR8 Human genes 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 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
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Abstract
This invention concerns pyrrolo[3,2-d]pyrimidine derivatives of formula (I), processes for their preparation, pharmaceutical compositions, and their use in treatment and /or therapy of diseases.
Description
/063467 Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases This invention relates to pyrrolo[3,2-d]pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treatment and /or therapy of diseases.
The present invention relates to the use of pyrrolo[3,2-d]pyrimidine derivatives more specifically to the use of pyrrolo[3,2-d]pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved. ike Receptors are primary transmembrane proteins terized by an extracellular leucine rich domain and a cytoplasmic extension that contains a conserved region. The innate immune system can recognize pathogen-associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of n pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on phagocytes.
This leads to the modulation of T cell our.
A majority of mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other ian species. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein ous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice s TLRs 11, 12, and 13, none of which are represented in humans. Other mammals may express TLRs which are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using mental animals as models of human innate immunity.
For reviews on toll-like receptors see the following journal articles. Hoffmann, J.A., Nature, 426, p33-38, 2003; Akira, S., Takeda, K., and , T., Annual Rev.
Immunology, 21, p335-376, 2003; ch, R. J., Nature Reviews: Immunology, 4, p512-520, 2004.
Compounds ting activity on Toll-Like receptors have been previously described such as heterocyclic derivatives in WO2000/006577, adenine tives in W098/01448 and W099/28321, and dines in W02009/O67081.
In the treatment of certain viral infections, regular injections of interferon (lFN-alfa) can be administered, as is the case for tis C virus (HCV). Orally available small molecule IFN inducers offer the potential ages of reduced immunogenicity and convenience of administration. Thus, novel IFN inducers are potentially effective new class of drugs for the treatment of viral infections. For an e in the literature of a small molecule IFN inducer having antiviral effect see De Clercq, E.; ps, J.; De Somer, P. Science 1978, 200, 563-565.
Interferon or is also given to patients in combination with other drugs in the treatment of certain types of cancer. TLR 7/8 agonists are also of interest as vaccine adjuvants because of their ability to induce pronounced Th1 response.
However, there exists a strong need for novel Toll-Like receptor modulators having preferred selectivity, and an improved safety profile compared to the compounds of the prior art.
In accordance with the present invention a compound of formula (I) is provided and their pharmaceutically acceptable salt, solvate or polymorph thereof wherein R1 is H, fluorine or methyl; R2 is H, halogen or C13 alkyl; R3 is 01-6 alkyl optionally substituted by one or more substituents independently selected from aryloxy, heterocycle, n, aryl, mino, dialkylamino, C143 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, nitrile, or 01-6 alkoxy; or wherein R3 is an alkylaryl optionally substituted by one or more substituents independently selected from n, aryloxy, aryl, alkylamino, dialkylamino, C143 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, amide, nitrile, or 01-6 ; R4 is 01-6 alkyl ally substituted by one or more substituents independently selected from hydroxyl, 01-6 alkyl, C37 lkyl, 02-6 alkenyl or aryl optionally further substituted by 01-3 alkyl, and C37 cycloalkyl ally further substituted by 01-6 alkyl; or n R4 is an alkylaryl optionally tuted by one or more substituents independently selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, sulfonamide, nitrile, or C 1-6 alkoxy, with the o that the compound does not satisfy any one of the following structural formulae: , ,and .
Preferred compounds are those of formula (I) n R3 is a CH2-aryl group (substituted or unsubstituted), and R1, R2, and R4 are described as above.
In a second embodiment are the compounds of formula (I) wherein R3 and R4 are both CH2-aryl groups ally further substituted as described above, and R1, and R2 are as described as above.
Other preferred embodiments are those of formula (I) wherein R1 is fluorine, R2 is hydrogen, and R3 and R4 are described as above.
The most preferred compound is compound of a (II) having the following chemical structure: (II) The compounds of formula (I) and (II) and their pharmaceutically acceptable salt, solvate or polymorph thereof have activity as pharmaceuticals, in particular as modulators of Toll-Like or (especially TLR7) activity. (followed by page 3a) -3a- In a particular aspect, the present invention provides the use of a compound of formula H2N N N N O R3 R4 (I) and their pharmaceutically acceptable salt, solvate or polymorph thereof wherein R1 is H, fluorine or methyl; R2 is H, n or C1-3 alkyl; R3 is C1-6 alkyl optionally substituted by one or more tuents independently selected from aryloxy, cycle, halogen, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, nitrile, or C1-6 alkoxy; or wherein R3 is an alkylaryl optionally substituted by one or more substituents ndently selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, ylic ester, carboxylic amide, sulfonamide, nitrile, or C 1-6 alkoxy; R4 is C1-6 alkyl optionally substituted by one or more substituents independently selected from hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or aryl optionally further substituted by C1-6 alkyl, and C3-7 cycloalkyl optionally further tuted by C1-6 alkyl; or wherein R4 is an alkylaryl optionally substituted by one or more substituents independently selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, sulfonamide, nitrile, or C1-6 , in the manufacture of a medicament for the treatment of a disorder in which the modulation of TLR7 is involved.
In a further aspect the present invention provides a pharmaceutical composition comprising a compound of a (I) or (II) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.
Furthermore a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or polymorph f ing to the current invention, or a pharmaceutical [FOLLOWED BY PAGE 4] composition comprising said compound of a (I) or (II) or a pharmaceutically acceptable salt, solvate or polymorph f can be used as a medicament.
Another aspect of the invention is that a compound of formula (I) or (II) or a ceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or ‘II) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used accordingly in the ent of any disorder in which the modulation of TLR7 is involved.
The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
The term "halogen" refers to fluorine, ne, bromine or iodine.
The term "alkylaryl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms tuted by an aryl wherein "aryl" is defined as below.
The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond.
The term "cycloalkyl" refers to a carbocyclic ring containing the ied number of carbon atoms.
The term "alkoxy" refers to an alkyl (carbon and hydrogen chain) group singular bonded to oxygen like for instance a methoxy group or ethoxy group.
The term "aryl" means an aromatic ring structure optionally comprising one or two atoms selected from N, O and S, in particular from N and O. Said aromatic ring structure may have 5, 6 or 7 ring atoms. In particular, said aromatic ring structure may have 5 or 6 ring atoms.
The term "aryloxy" refers to an aromatic ring ure. Said aromatic group is singularly bonded to oxygen.
The term "heterocycle" refers to molecules that are saturated or partially saturated and include tetrahydrofuran, e or other cyclic ethers. Heterocycles containing nitrogen include, for example azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
Pharmaceutically acceptable salts of the compounds of formula (I) and (II) include the acid on and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form non- toxic salts.
The compounds of the invention may also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
The term "polymorph" refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
The compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other nds of the invention or in combination with one or more other drugs.
Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable ents. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
The compounds of the present invention or any subgroup thereof may be formulated into various ceutical forms for administration es. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is ed in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These ceutical compositions are bly in unitary dosage form le, for e, for oral, rectal, or aneous administration. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid rs such as starches, sugars, kaolin, ts, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. e of their ease in administration, tablets and es represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously ed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms. In the compositions suitable for percutaneous administration, the carrier optionally ses a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable ves of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the stration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present ion may be administered to the lungs in the form of a solution, a suspension or a dry powder.
It is especially advantageous to formulate the aforementioned pharmaceutical itions in unit dosage form for ease of administration and uniformity of dosage.
Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated s), capsules, pills, powder s, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the ent of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general it is plated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for e, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of a (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other tion the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount may be lowered or increased ing on the response of the treated subject and/or ing on the tion of the physician prescribing the compounds of the instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
Experimental Section Scheme 1. Overall reaction scheme HOAR N H o\ 1N NaOH / |NYNTO / | \Y T —> N TRIPHENYLPHOSPHINE RESIN, N / N O H gfg'osxfne’ DIAD, THF,RT,1h CI J R CI A B HO/\ N NH2 R1 N NH2 / I Y / | Y RJ NaH 60%, NMP, CI R 05°C, 30' then RT 2h O\R1 C D Compounds of type A in scheme 1 can be functionalized with alcohols using Mitsunobu ions in a polar aprotic solvent, for example THF. The cleavage of the methyl carbamate was performed under basic conditions in 1,4-dioxane to form intermediate C.
The displacement of the chlorine in C was performed with an alcohol and a base (e.g.
NaH) in a polar aprotic solvent (e.g. NMP) to form compounds of the type D.
Preparation of intermediate A H O O O O- —> \/ o +OZ/‘< H+ Na" /\ 0— MeOH, RT,16h HN POCI3 "N m o a lift HO NANJLO/ DIPEA, CH3CN, 70°C C. N’ m o/ oethoxycarbonylpyrrole hydrochloride (25.8 g, 135.3 mmol) was ioned between dichloromethane and sat. NaHC03. The organic layer was dried over MgSO4, the solids were removed via filtration, and the solvent of the filtrate evaporated to dryness. The residue was dissolved in methanol (500 mL) together with 1,3- bis(methoxycarbonyl)methylthiopseudourea (32.1 g, 156 mmol) and acetic acid (39 mL, 677 mmol) and stirred 1 hour at room temperature. A precipitate appeared and stirring was continued overnight. Sodium methoxide (73.1 g, 1353 mmol) was added.
An exothermic reaction was observed and the reaction mixture was stirred overnight.
The mixture was t to pH 5 with acetic acid and the precipitate was isolated by filtration, triturated on the filter with water (2 x 350 mL), acetonitrile (350 mL) and diisopropylether (350 mL). The obtained methyl N-(4-hydroxy-5H-pyrrolo- [3,2-d]pyrimidinyl)carbamate was dried in the oven. methyl N-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidinyl)carbamate (25 g, 120 mmol) was dispensed in 350 mL acetonitrile in a 500 mL multi neck flask equipped with with an ad stirrer (300 rpm) at room temperature. POCI3 (22.1 mL, 238.2 mmol) was added and then the reaction e was heated to 70°C while ng.
Diisopropylethylamine (41.4 mL, 240.2 mmol) was added dropwise via a syringe pump at a flow of 0.2 mL/min.
The reaction mixture was cooled to room temperature and poured into a stirred solution of sodium acetate (78.8 g, 961 mmol) in water (500 mL) at 45°C. The organics were evaporated and the remaining liquid was stirred and cooled over an ice bath. The formed solid was isolated by filtration, washed with acetonitrile and triturated with diisopropylether to afford intermediate A, dried under . LC-MS m/z = 227 (M+H) Preparation of intermediate B Method 1.
HN DIAD ah \N 0 I + Cl / THF, rt 0/ 30min A B To a suspension of A (500 mg, 2.2 mmol), benzylalcohol (0.28 mL, 2.6 mmol) and triphenylphosphine (0.69 g, 2.6 mmol) in anhydrous THF (15 mL) was added DIAD (0.64 mL, 3.3 mmol) at room temperature. The on mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure.
The product was purified via silica gel column tography using a heptanes to ethyl acetate gradient; 100-0 to 90-10. The product fractions were collected and concentrated under reduced pressure. The t was triturated in diisopropylether, isolated by filtration and dried under vacuum to afford B as a pale yellow solid. LC-MS m/z = 317 (M+H) Method 2 with resin bound triphenylphosphine.
To a suspension of A (700 mg, 3.1 mmol), benzylalcohol (0.39 mL, 3.7 mmol) and triphenylphosphine resin (2.6 g, 7.7 mmol) in ous THF (21 mL) was added DIAD (0.90 mL, 4.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1h. The mixture was filtered over packed decalite and washed with methanol. The filtrate was trated in vacuo. The product was triturated in diisopropylether, isolated by filtration and dried under vacuum to afford a pale yellow solid, B. LC-MS m/z = 317 (M+H) Preparation of intermediate C Q/ ~ 1N NaOH \N O Q/NI I 1 ,4-dioxane, 60°C, 5h CI NAN H 2 CI NANJLO/ B (738 mg, 2.3 mmol) was dissolved in 1,4-dioxane (11 mL) in a 50 mL glass tube and NaOH (5.6 mL, 1N a.q.) was added. The mixture was heated to 60°C for 5h. The mixture was cooled and concentrated in vacuo. The residue was treated with water and the precipitate was ed by filtration and dried under vacuum to afford C as a solid.
The product was used as such in the next step. LC-MS m/z = 259 (M+H) Preparation of 1 and 2 Method 1.
Q/ ~ HCI 4N in Dioxane N HO/\/\ I MW120°C 10min—>N‘|\J\Q/ C N/)\NH2 c 1 Intermediate C (240 mg, 0.93 mmol), n-butylalcohol (3.2 mL, 35 mmol), and 4N HCI in dioxane (0.46 mL, 1.9 mmol) was placed into a 7 mL microwave vial. The vial was sealed and the mixture was heated in the microwave at 120°C for 10 minutes. The mixture was cooled and concentrated in vacuo. The residue was neutralized with sat.
NaHC03 solution and extracted with dichloromethane. The c layer was separated, dried (MgSO4), the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The t was purified via silica gel column chromatography using a dichloromethane-methanol;100-0 to 95-5 gradient. The best fractions were collected and trated under d pressure. The product was triturated in diisopropylether and the solid was isolated by filtration and dried under vacuum to afford 1 as a white solid.
Method 2.
N, \O/\/N‘ \o/\/ \ N NaH 60% \N \ )\ I\ | N/ NH2 —’ + N\ A 0 O N c1 NMP, 06°C, 30' then RT2h ""2 OI \ Intermediate C2 (250 mg, 1.1 mmol), and 3-hydroxymethylmethylisoxazole (0.16 mL, 1.65 mmol) were dissolved in NMP (3 mL) in a 7 mL vial. The mixture was cooled on a ice bath and NaH (66 mg, 1.65 mmol, 60% dispersion in mineral oil) was added under N2 and the mixture was stirred at 0-5 °C for 30 s and then allowed to warm to room ature and continued stirring for 2h. Then crude reaction mixture was purified by preparatory HPLC (Stationary phase: RP Vydac Denali C18 10 pm, 200 g, 5 cm), mobile phase: 0.25% NH4OAc solution in water, CH3CN), the desired fractions were collected and concentrated in vacuo. The product was crystallized from CH3CN, isolated by filtration and dried under vacuum to afford a white solid, 2.
Table 1. Compounds of formula (I) and corresponding analytical data. Compounds were prepared according to the methods described in the experimental section.
LC Method, LC-MS Mass # URE 1 H NMR Rt (min). Found (M+H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.85 (t, J=7.37 Hz, 3 H) < 2 - 1.26 (dq, J=15.02, 7.39 Hz, 2 H) 1.56 - 1.63 (m, 2 H) 4.30 (t, AHZ J=6.38 Hz, 2 H) 5.39 (s, 2 H) B, 1.98 297 .72 (s, 2 H) 6.08 (d, J=3.08 Hz, 1 H) 7.03 - 7.08 (m, 2 H) 7.19 - 7.25 (m, 1 H) 7.26 - 7.32 (m, 2 H) 7.48 (d, J=3.08 Hz, 1 H) 1H NMR (400 MHz, DMSO- d6) 5 ppm 2.41 (d, J=0.66 Hz, 3 H) \N 3.17 (s, 3 H) 3.57 (t, J=5.50 Hz, AHZ 2 H) 4.29 (t, J=5.50 Hz, 2 H) 5.50 A, 0.69 304 (s, 2 H) 5.82 (s, 2 H) 6.03 (d, J=2.86 Hz, 1 H) 6.37 (d, J=0.88 Hz, 1 H)7.35 (d, J=2.86 Hz, 1 H) 1H NMR (400 MHz, DMSO- d6) 5 q: ppm 2.33 - 2.38 (m, 3 H) 3.79 (s, 3H)534(s 2H)538(s 2H) INJ‘NHz 5.7,5(s1H)586(s 2H)6.12 (d, J:3.0,8Hz 1 - 6.47 B, 1.62 366 (m, 1 H) 6.78 (td, J=7.48, 0.66 Hz, 1 H)7.00 (d, J=7.92 Hz, 1 H) 7.24 (td, J=7.80, 1.80 Hz, 1 H) 7.43 (d, J=2.86 Hz, 1 H) -1 2- LC Method, LC-MS Mass # STRUCTURE 1H NMR Rt (min) Found (M+H) 1H NMR (400 MHz, DMSO-de) 5 ppm 0.77 (t, J=7.4 Hz, 3 H), 1.12 / (dq, J=15.0, 7.4 Hz, 2 H), 1.40 - \N / 1.50 (m, 2 H), 4.21 (t, J=6.4 Hz, | 2 H), 5.49 (s, 2 4 9 AH, (s, 2 H), 5.73 6 A, 0.81 298 f H), 6.11 (d, J—2.9 Hz, 1 H), 6.65 (d, J=7.9 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.47 (d, J=3.1 Hz, 1 H), 7.69 (td, J=7.7, 1.8 Hz, 1 H), 8.47 - 8.53 (m, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 2.35 (s, 3 H) 5.37 (s, 2 H) / 5.47 (s, 2 H) 5.84 - 5.90 (m, 3 H) N 6.14 (d, J=2.86 Hz, 1 H) 6.72 (d, J=7.92 Hz, 1 H) 7.24 (dd, B, 1.29 337 _, J=6.93, 4.95 Hz, 1 H) 7.52 (d, J=3.08 Hz, 1 H) 7.65 (td, J=7.70, 1.76 Hz, 1 H) 8.47 (d, J=4.18 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 2.57 (s, 3 H) 5.45 (s, 2 H) / 5.51 (s, 2 H) 5.85 (s, 2 H) 6.13 N (d, J=2.86 Hz, 1 H) 6.85 (d, J=7.70 Hz, 1 H) 7.22 (dd, B, 1.14 338 >=N , 5.06 Hz, 1 H) 7.52 (d, J=3.08 Hz, 1 H) 7.64 (td, J=7.65, 1.65 Hz, 1 H) 8.43 (d, J=4.18 Hz, 1 H) LC Method, LC-MS Mass # URE 1 H NMR Rt (min) Found (M+H) 1H NMR (400 MHz, DMSO-ds) 5 /0 ppm 2.36 (s, 3 H) 3.74 (s, 3 H) C," 3.71 ‘ (s, 3 H)5.29 (s, 2 H)5.40 7 "39% (s, 2 H) 5.85 (s, 2 H) 5.93 (s, 1 B 1.45 397 0 HM H) 6.12 (d, J=3.08 Hz, 1 H) 6.29 02k (d, J=7.92 Hz, 1 H)7.11 (d, J=7.92 Hz, 1 H) 7.50 (d, J=3.08 Hz, 1 H) 1H NMR (400 MHz, DMSO- d6) 5 q _ ppm 2.36 (s, 3 H) 3.80 (s, 3 H) .31 o\ \N (s, 2 H) 5.48 (s, 2 H) 5.75 - 8 o N/ H: 5.81 (m, 3 H) 6.07 (d, J=2.86 Hz, A, 0.72 367 07k 1 H) 7.25 (dd, J=8.25, 4.73 Hz, 1 H) 7.36 - 7.41 (m, 2 H) 7.90 (dd, J=4.73, 0.99 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 ppm 2.23 (d, J=1.10 Hz, 3 H) N 3.77 (s, 3 H) 5.32 (s, 2 H) 5.45 N‘ (s,2 H)5.77 (s,2 H)6.07 (d, 9 A; | :" J=2.86 Hz, 1 H)6.79 (d,J=1.10 B, 1.26 367 yr» N "2 Hz, 1 H)7.21 (dd, J=8.25, 4.73 Hz, 1 H) 7.33 (dd, J=8.36, 1.32 Hz, 1 H)7.37 (d, J=2.86 Hz, 1 H) 7.88 (dd, J=4.73, 1.21 Hz, 1 H) 1H NMR (400 MHz, DMSO-ds) 5 N ppm 2.34 - 2.41 (m, 3 H) 5.49 (s, \ I ‘ 2 H) 5.58 (s, 2 H) 5.88 (s, 2 H) N | l 6.15(d,J=2.86 Hz, 1 H)6.72 (d, B, 1.28 353 V0 / N Hz J=7.92 Hz, 1 H)7.20- 7.25 (m, 1 H) 7.43 (d, J=1.10 Hz, 1 H) 7.52 (d, J=2.86 Hz, 1 H) 7.63 (td, J=7.70, 1.76 Hz, 1 H) 8.46 (dd, WO 07082 LC Method, LC-MS Mass # STRUCTURE 1 H NMR Rt (min). Found (M+H) J=4.73, 0.77 Hz, 1 H) 1H NMR (400 MHz, DMSO-de) 5 ppm 2.24 (s, 3 H) 5.39 (s, 2 H) //N 5.43 (s, 2 H) 5.85 (s, 2 H) 6.13 \ ‘ (d, J=2.86 Hz, 1 H) 6.76 (d, N | J=7.70 Hz, 1 H)6.81 (s, 1 H) B, 1.18 337 Sj/N) / N Hz 7.21 (dd, J=6.93, 5.17 Hz,1 H) 7.52 (d, J=2.86 Hz, 1 H) 7.62 (td, J=7.65, 1.43 Hz, 1 H) 8.40 - 8.45 (m, 1 H) Analytical Methods.
LCMS General Procedure The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, onal detectors were included (see table of methods below).
Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the d person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compounds nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate re.
Compounds are described by their experimental retention times (Rt) and ions. If not ied differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H]— (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is ied (i.e. [M+NH4]+, [M+HCOO]—, etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one ed for the lowest isotope mass. All results were obtained with mental uncertainties that are commonly associated with the method used.
Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "RT" room temperature, "BEH" bridged ethylsiloxane/silica hybrid, "DAD" Diode Array or, "HSS" High Strength silica., "Q-Tof’ Quadrupole f-flight mass spectrometers, "CLND", uminescent Nitrogen Detector, "ELSD" ative Light Scanning Detector, LC-MS Method codes (Flow sed in mL/min; column temperature (Col T) in °C; Run time in s).
Instrument Column Mobile phase Gradient A: 10mM Waters: Waters: CH3COONH4 From 95% A Acquity® BEH C18 in 95% H20 + to 5% A in UPLC®-DAD (1.7um, 5% CH3CN 1.3 min, held and SQD 2.1*50mm) for 0.7 min.
B: CH3CN A: 10mM From 100% Waters: Waters: CH3COONH4 Ato 5% A in Acquity® HSS T3 in 95% H20 + 2.10min, to UPLC®-DAD (1.8um, 5% CH3CN 0% A in 0.90 and SQD 2.1*100mm) min, to 5% A B: CH3CN in 0.5min Biolo ical t of com ounds of formula I and II Description of Biological Assays Assessment of TLR7 and TLR8 activity The ability of compounds to activate human TLR7 and/or TLR8 was assessed in a cellular reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 expression vector and NFKB-IUC reporter construct.
Briefly, HEK293 cells were grown in culture medium (DMEM supplemented with 10% FCS and 2 mM Glutamine). For transfection of cells in 15 cm dishes, cells were detached with Trypsin-EDTA, transfected with a mix of CMV-TLR7 or TLR8 plasmid WO 07082 (1700 ng), NFKB-IUC plasmid (850 ng) and a transfection reagent and incubated for 48 h at 37°C in a humidified 5% C02 atmosphere. Transfected cells were then washed in PBS, detached with Trypsin-EDTA and resuspended in medium to a density of 1.25 X 105 cells/mL. Forty microliters of cells were then dispensed into each well in ll plates, where 200 nL of compound in 100% DMSO was already present. Following 6 hours incubation at 37°C, 5% C02, the luciferase activity was determined by adding 15 uL of Steady Lite Plus substrate (Perkin Elmer) to each well and readout performed on a ViewLux ultraHTS microplate imager (Perkin Elmer). Dose response curves were generated from measurements performed in quadruplicates. Lowest effective concentrations (LEC) values, defined as the concentration that induces an effect which is at least two fold above the standard ion of the assay, were determined for each compound.
Compound toxicity was determined in el using a similar dilution series of compound with 40 uL per well of cells transfected with the R7 construct alone (1.25 x 105 cells/mL), in 384-well plates. Cell viability was measured after 6 hours incubation at 37°C, 5% C02 by adding 15 uL of ATP lite (Perkin Elmer) per well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported as 0050.
In parallel, a similar dilution series of compound was used (200 nL of compound in 100% DMSO) with 40 uL per well of cells transfected with NFkB-luc reporter construct alone (1.25 x 105 cells/mL). Six hours after incubation at 37°C, 5% C02, the luciferase activity was determined by adding 15 uL of Steady Lite Plus substrate (Perkin Elmer) to each well and readout performed on a ViewLux ultraHTS microplate imager (Perkin Elmer). Counterscreen data is ed as LEC.
Activation of ISRE er elements The potential of compounds to induce lFN-l was also evaluated by measuring the activation of interferon-stimulated responsive elements (ISRE) by conditioned media from PBMC. The ISRE element of sequence GAAACTGAAACT is highly responsive to the STAT1-STAT2-IRF9 transcription factor, activated upon binding of lFN-l to their receptor IFNAR ech, PT3372-5W). The d plSRE-Luc from Clontech (ref. 631913) contains 5 copies of this ISRE element, ed by the firefly luciferase ORF.
A HEK293 cell line stably transfected with plSRE-Luc (HEK-lSREluc) was established to e the conditioned PBMC cell culture media.
Briefly, PBMCs were ed from buffy coats of at least two donors using a standard Ficoll centrifugation protocol. lsolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 105 cells/well were dispensed into 384-well plates containing compounds (70 uL total volume). After overnight incubation, uL of supernatant was transferred to 384-well plates containing 5 X 103 HEK-lSREluc cells/well in 30 uL (plated the day before). Following 24 hours of incubation, activation of the ISRE elements was measured by assaying luciferase activity using 40 uL/well Steady Lite Plus substrate (Perkin Elmer) and measured with ViewLuX TS microplate imager (Perkin Elmer). The ating activity of each compound on the HEK-lSREluc cells was reported as LEC value, defined as the compound concentration applied to the PBMCs resulting in a luciferase activity at least two fold above the rd deviation of the assay. The LEC in turn indicates the degree of ISRE activation on transfer of a d amount of PBMC culture medium. inant interferon d-2a (Roferon-A) was used as a standard control compound.
Table 2. Activity of compounds of formula (I).
All compounds demonstrated a CC50 >24uM.
Human TLR 7 (LEC) Human TLR 8 HEK-ISRE luc uM (LEC) uM (LEC) uM 1 0.6 >25 0.4 2 2.7 >25 0.5 3 0.1 >25 0.03 4 1.4 >25 0.6 0.4 >25 0.1 6 3.9 >25 2 7 0.08 >25 0.03 8 0.03 >25 0.01 9 0.07 >25 NA WO 07082 Human TLR 7 (LEC) Human TLR 8 HEK-ISRE luc "M (LEC) "M (LEC) "M 0.5 >25 NA 11 0.6 >25 NA NA = not available
Claims (12)
1. A compound of formula (I) H2N N N N O R3 R4 (I) and their pharmaceutically able salt, e or polymorph thereof wherein 5 R1 is H, fluorine or methyl; R2 is H, halogen or C1-3 alkyl; R3 is C1-6 alkyl optionally substituted by one or more substituents ndently selected from aryloxy, heterocycle, halogen, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, nitrile, or C1-6 ; 10 or wherein R3 is an alkylaryl optionally substituted by one or more tuents independently selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, sulfonamide, nitrile, or C1-6 alkoxy; R4 is C1-6 alkyl optionally substituted by one or more substituents independently 15 selected from hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or aryl optionally further substituted by C1-6 alkyl, and C3-7 cycloalkyl ally further substituted by C1-6 alkyl; or wherein R4 is an alkylaryl optionally substituted by one or more substituents independently 20 selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, ylic amide, sulfonamide, e, or C1-6 alkoxy, with the proviso that the compound does not satisfy any one of the following structural formulae: , ,and .
2. A compound according to claim 1 wherein R3 is a CH2-aryl group (substituted or unsubstituted), and R1, R2, and R4 are described as in claim 1. 5
3. A compound of a (I) wherein R3 and R4 are both CH2-aryl groups optionally further substituted as described in claim 1, and n R1, and R2 are as described in claim1.
4. A compound according to claim 1 wherein R1 is fluorine, R2 is en, and R3 and 10 R4 are described as in claim 1.
5. A compound according to claim 1 having the following chemical structure:
6.(II). 15 6. A compound according to claim 1, wherein the compound satisfies any one of the following formulae: , , , , ,, , , , and . 5
7. A pharmaceutical composition comprising a compound of formula (I) or (II) or a ceutically acceptable salt, solvate or polymorph thereof according to claim 1, 5 or 6 er with one or more pharmaceutically acceptable excipients, diluents or carriers. 10
8. A compound of a (I) or (II) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to claim 1, 5 or 6, or a pharmaceutical composition comprising said compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or rph thereof according to claim 7 for use as a medicament. 15
9. Use of a compound of formula (I) or (II) or a ceutically acceptable salt, solvate or polymorph thereof according to claim 1, 5 or 6 or said pharmaceutical composition comprising said compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to claim 7 in the manufacture of a ment for treatment of any disorder in which the modulation of TLR7 is involved.
10. The use of a compound of formula (I) H2N N N N O R3 5 R4 (I) and their pharmaceutically able salt, solvate or polymorph thereof wherein R1 is H, ne or methyl; R2 is H, halogen or C1-3 alkyl; R3 is C1-6 alkyl optionally substituted by one or more substituents independently selected 10 from y, heterocycle, halogen, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, nitrile, or C1-6 ; or wherein R3 is an ryl ally substituted by one or more substituents independently selected from halogen, aryloxy, aryl, alkylamino, dialkylamino, C1-6 alkyl, ylic acid, 15 carboxylic ester, carboxylic amide, sulfonamide, nitrile, or C 1-6 alkoxy; R4 is C1-6 alkyl optionally substituted by one or more substituents independently selected from hydroxyl, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or aryl optionally further substituted by C1-6 alkyl, and C3-7 cycloalkyl optionally further substituted by C1-6 alkyl; or wherein R4 is an alkylaryl optionally substituted by one or more substituents 20 independently selected from halogen, y, aryl, alkylamino, dialkylamino, C1-6 alkyl, carboxylic acid, carboxylic ester, carboxylic amide, sulfonamide, nitrile, or C1-6 alkoxy, in the manufacture of a medicament for the treatment of a disorder in which the modulation of TLR7 is involved. 25
11. The compound of claim 1, substantially as herein described with reference to any one of the Examples thereof.
12. The use of claim 10, ntially as herein described with reference to any one of the Examples thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ754320A NZ754320B2 (en) | 2014-06-26 | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13174108.4 | 2013-06-27 | ||
EP13174108 | 2013-06-27 | ||
PCT/EP2014/063467 WO2014207082A1 (en) | 2013-06-27 | 2014-06-26 | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ714267A NZ714267A (en) | 2021-06-25 |
NZ714267B2 true NZ714267B2 (en) | 2021-09-28 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018274911B2 (en) | Pyrrolo[3,2-c]Pyrimidine derivatives for the treatment of viral infections and other diseases | |
AU2013328732B2 (en) | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases | |
DK2812331T3 (en) | PIPERIDINOPYRIMIDINE DERIVATIVES FOR TREATING VIRUS INFECTIONS | |
US9284304B2 (en) | Substituted pyrimidines as toll-like receptor modulators | |
AU2013326579B2 (en) | 1,2,4-triazine derivatives for the treatment of viral infections. | |
CA3027471A1 (en) | Dihydropyranopyrimidines for the treatment of viral infections | |
JP2015537020A (en) | Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections | |
AU2014270418B2 (en) | Pyridone derivatives for the treatment of viral infections and further diseases | |
NZ714267B2 (en) | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases | |
NZ754320B2 (en) | Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases | |
EA040150B1 (en) | METHOD FOR OBTAINING PYRROLO[3,2-D]PYRIMIDINE DERIVATIVES | |
NZ713679B2 (en) | Pyridone derivatives for the treatment of viral infections and further diseases |