CA2116782C - 1-substituted 1h-imidazo¬4,5-c|quinolin-4-amines; intermediate and pharmaceutical compositions - Google Patents
1-substituted 1h-imidazo¬4,5-c|quinolin-4-amines; intermediate and pharmaceutical compositions Download PDFInfo
- Publication number
- CA2116782C CA2116782C CA002116782A CA2116782A CA2116782C CA 2116782 C CA2116782 C CA 2116782C CA 002116782 A CA002116782 A CA 002116782A CA 2116782 A CA2116782 A CA 2116782A CA 2116782 C CA2116782 C CA 2116782C
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- Prior art keywords
- carbon atoms
- group
- alkyl
- alkoxy
- hydrogen
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- -1 1-alkynyl Chemical group 0.000 claims abstract description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 claims abstract description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 4
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 102000014150 Interferons Human genes 0.000 claims description 20
- 108010050904 Interferons Proteins 0.000 claims description 20
- 229940079322 interferon Drugs 0.000 claims description 20
- 150000002431 hydrogen Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 241000700605 Viruses Species 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 230000000840 anti-viral effect Effects 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- MKGQISHSWGSSII-UHFFFAOYSA-N 1-(oxan-2-ylmethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=NC=2C(N)=NC3=CC=CC=C3C=2N1CC1CCCCO1 MKGQISHSWGSSII-UHFFFAOYSA-N 0.000 claims description 3
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 3
- 125000005333 aroyloxy group Chemical group 0.000 claims description 3
- ZUFWIFXSWOUWOX-UHFFFAOYSA-N 1-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C3N(COCC)C=NC3=C(N)N=C21 ZUFWIFXSWOUWOX-UHFFFAOYSA-N 0.000 claims description 2
- FBLQCKKSSYICML-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=NC=2C(N)=NC3=CC=CC=C3C=2N1CC1=CC=CC=N1 FBLQCKKSSYICML-UHFFFAOYSA-N 0.000 claims description 2
- IAABTIQDDBOQTO-UHFFFAOYSA-N 1-(pyridin-4-ylmethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=NC=2C(N)=NC3=CC=CC=C3C=2N1CC1=CC=NC=C1 IAABTIQDDBOQTO-UHFFFAOYSA-N 0.000 claims description 2
- CEOVNVPMHCCQPZ-UHFFFAOYSA-N 1-prop-2-ynylimidazo[4,5-c]quinolin-4-amine Chemical compound NC1=NC2=CC=CC=C2C2=C1N=CN2CC#C CEOVNVPMHCCQPZ-UHFFFAOYSA-N 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- ICBPTRWBZCYWDC-UHFFFAOYSA-N 1-(2-methoxyethyl)-2-methylimidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C3N(CCOC)C(C)=NC3=C(N)N=C21 ICBPTRWBZCYWDC-UHFFFAOYSA-N 0.000 claims 1
- FUDDFDBDWOILEX-UHFFFAOYSA-N 1-(2-methoxypropyl)-2-methylimidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C3N(CC(C)OC)C(C)=NC3=C(N)N=C21 FUDDFDBDWOILEX-UHFFFAOYSA-N 0.000 claims 1
- 208000009889 Herpes Simplex Diseases 0.000 claims 1
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- 238000002360 preparation method Methods 0.000 abstract description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract description 5
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
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- 238000007429 general method Methods 0.000 description 11
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- 239000002244 precipitate Substances 0.000 description 11
- HQBUPOAKJGJGCD-UHFFFAOYSA-N 3h-imidazo[4,5-c]quinolin-4-amine Chemical class NC1=NC2=CC=CC=C2C2=C1N=CN2 HQBUPOAKJGJGCD-UHFFFAOYSA-N 0.000 description 10
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 241000700198 Cavia Species 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- 150000001204 N-oxides Chemical class 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
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- 239000008280 blood Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical class C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 description 5
- 239000012320 chlorinating reagent Substances 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- ZWISCKSGNCMAQO-UHFFFAOYSA-N 3-nitro-1H-quinolin-4-one Chemical class C1=CC=C2C(=O)C([N+](=O)[O-])=CNC2=C1 ZWISCKSGNCMAQO-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- ZRFUZDDJSQVQBY-UHFFFAOYSA-N 4-chloro-3-nitroquinoline Chemical compound C1=CC=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 ZRFUZDDJSQVQBY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- IRUNKQSGDBYUDC-UHFFFAOYSA-N diethoxymethyl acetate Chemical compound CCOC(OCC)OC(C)=O IRUNKQSGDBYUDC-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 150000002905 orthoesters Chemical class 0.000 description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- KNZZCVKZUHYLQH-UHFFFAOYSA-N 1-(2-methoxypropyl)-2-methylimidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(CC(C)OC)C(C)=NC3=CN=C21 KNZZCVKZUHYLQH-UHFFFAOYSA-N 0.000 description 2
- RSFJVCHKGRUCIC-UHFFFAOYSA-N 2,4-dichloro-3-nitroquinoline Chemical compound C1=CC=CC2=C(Cl)C([N+](=O)[O-])=C(Cl)N=C21 RSFJVCHKGRUCIC-UHFFFAOYSA-N 0.000 description 2
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- DDMPXUWRBYMDTG-UHFFFAOYSA-N 4-chloro-1-(pyridin-4-ylmethyl)imidazo[4,5-c]quinoline Chemical compound C1=NC=2C(Cl)=NC3=CC=CC=C3C=2N1CC1=CC=NC=C1 DDMPXUWRBYMDTG-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
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- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- 239000003480 eluent Substances 0.000 description 2
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- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- NSHFLKZNBPJNPA-UHFFFAOYSA-N imidazo[4,5-c]quinolin-2-one Chemical class C1=CC=C2C3=NC(=O)N=C3C=NC2=C1 NSHFLKZNBPJNPA-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 2
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- XBTKUKLVUPZNQB-UHFFFAOYSA-N n-(2-methoxyethyl)-3-nitroquinolin-4-amine Chemical compound C1=CC=C2C(NCCOC)=C([N+]([O-])=O)C=NC2=C1 XBTKUKLVUPZNQB-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
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- YJKZDGOMTKOYQK-UHFFFAOYSA-N 1-(2-piperidin-4-ylethyl)imidazo[4,5-c]quinoline Chemical compound C1=NC2=CN=C3C=CC=CC3=C2N1CCC1CCNCC1 YJKZDGOMTKOYQK-UHFFFAOYSA-N 0.000 description 1
- HDDNSPWJCZZICL-UHFFFAOYSA-N 1-(6-methoxyquinolin-8-yl)-2-methylimidazo[4,5-c]quinoline Chemical compound N1=CC=CC2=CC(OC)=CC(N3C4=C5C=CC=CC5=NC=C4N=C3C)=C21 HDDNSPWJCZZICL-UHFFFAOYSA-N 0.000 description 1
- VCBYEQBFSSCIQJ-UHFFFAOYSA-N 1-(ethoxymethyl)imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C3N(COCC)C=NC3=CN=C21 VCBYEQBFSSCIQJ-UHFFFAOYSA-N 0.000 description 1
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- UNKWUGLQVWMUGK-UHFFFAOYSA-N 2-chloro-4-n-(pyridin-2-ylmethyl)quinoline-3,4-diamine Chemical compound NC1=C(Cl)N=C2C=CC=CC2=C1NCC1=CC=CC=N1 UNKWUGLQVWMUGK-UHFFFAOYSA-N 0.000 description 1
- DITYRCCGBOTQMI-UHFFFAOYSA-N 2-chloro-4-n-(pyridin-4-ylmethyl)quinoline-3,4-diamine Chemical compound NC1=C(Cl)N=C2C=CC=CC2=C1NCC1=CC=NC=C1 DITYRCCGBOTQMI-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- SVNCRRZKBNSMIV-UHFFFAOYSA-N 3-Aminoquinoline Chemical group C1=CC=CC2=CC(N)=CN=C21 SVNCRRZKBNSMIV-UHFFFAOYSA-N 0.000 description 1
- ZXVRNZRQQRBDLX-UHFFFAOYSA-N 3-nitroquinoline Chemical compound C1=CC=CC2=CC([N+](=O)[O-])=CN=C21 ZXVRNZRQQRBDLX-UHFFFAOYSA-N 0.000 description 1
- HDHQZCHIXUUSMK-UHFFFAOYSA-N 4-hydroxy-2-quinolone Chemical compound C1=CC=C2C(O)=CC(=O)NC2=C1 HDHQZCHIXUUSMK-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- XGNGQJXCUMPRHN-UHFFFAOYSA-N 7-chloro-4-hydroxy-1h-quinolin-2-one Chemical compound C1=C(Cl)C=C2NC(O)=CC(=O)C2=C1 XGNGQJXCUMPRHN-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
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- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
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- 102000006992 Interferon-alpha Human genes 0.000 description 1
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- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LUTSRLYCMSCGCS-BWOMAWGNSA-N [(3s,8r,9s,10r,13s)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,16-decahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC=C3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 LUTSRLYCMSCGCS-BWOMAWGNSA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- HDUHSISAGHHYRW-UHFFFAOYSA-N [N].N1=CC=CC2=CC=CC=C21 Chemical compound [N].N1=CC=CC2=CC=CC=C21 HDUHSISAGHHYRW-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000002943 spectrophotometric absorbance Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compounds of formula (I) wherein R'1 is hydrogen or a carbon-carbon bond, with the proviso that when R'1 is hydrogen R1 is alkoxy, hydroxyalkoxy, 1-alkynyl, tetrahydropyranyl, alkoxyalkyl, 2-, 3-, or 4-pyridyl, and with the further proviso that when R'1 is a carbon-carbon bond R'1 and R1 together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl, active as immunnomodulators and antiviral agents. Also, intermediate in the preparation of such compounds.
Description
2 PC1'/US92/07226 '?
1-SUBSTITUTED IH-IMIDAZO(4,5-C)QUINOLIN-4-AMINES; INTERMEDIATE AND PHARMACEUTI-CAL COMPOSITIONS
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to 1H-imidazo[4,5-c]-_ quinoline compounds. In other aspects, this invention relates to 1H-imidazo[4,5-c]quinolin-4-amines, intermediates for the preparation of such compounds, pharmaceutical compositions containing such compounds, and pharmacological methods of using such compounds.
Description of the Related Art The first reliable report of the 1H-imidazo-[4,5-c]quinoline ring system, Backman et al., J. Org.
Chem. 15, 1278-1284 (1950), describes the synthesis,of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]-quinoline for possible use as an antimalarial agent.
Subsequently; syntheses of various substituted 1H-imidazo[4,5-c]quinolines have been reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), has synthesized the compound 1-[2-(4-piperidyl)ethyl]-iH-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent.
Also, Baranov et al., Chem. Abp: 85, 94362.(1976), has reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chew. 18, 1537-1.540 (1981), has reported certain 2-oxoimidazo[4,5-c]-quinolines.
Certain antiviral 1H-imidazo[4,5-c]quinolin-4-amines are described in U.S. Pat. No. 4,689,338 (Gerster). These compounds are substituted on the 1-position by alkyl, hydroxyalkyl, acyloxyalkyl, benzyl, phenylethyl or substituted phenylethyl, and at the 2-position with hydrogen, alkyl, benzyl, or substituted benzyl, phenylethyl or phenyl. .
Furthermore, these compounds are known to induce interferon biosynthesis. Other antiviral 1H-imidazo[4,5-c)quinolin-4-amines, substituted on the 1-position by alkenyl substituents, are described in U.S. Pat. No. 4,929,624 (Gersterj.
U.S. Pat. No. 4,698,348 (Gersterj discloses iH-imidazo[4,5-c)quinolines that are active as bronchodilators, such as 4-substituted 1H-imidazo-[4,5-c]quinolines wherein the 4-substituent is, inter alia, hydrogen, chloro, alkylamino, or dialkylamino, and the 2-substituent is, inter alia, hydroxyalkyl, aminoalkyl, or alkanamidoalkyl. Said patent also discloses 3-amino and 3-nitro quinoline intermediates substituted at the 4-position by hydroxyalkylamino or cyclohexylmethylamino, and iH-imidazo[4,5-c)quinoline N-oxide intermediates substituted at the 2-position with, inter alia, hydroxyalkyl, aminoalkyl, or alkanamidoalkyl.
DETAILED DESCRIPTION OF THE INVENTION
This invention as broadly described hereinafter provides compounds of Forumula I:
NHS
N
N
N
i CHR1R'~
R
wherein R'1 is hydrogen or a carbon-carbon bond, with the proviso that when R', is hydrogen Ri is alkoxy of one tv about four carbon atoms, hydroxyalkoxy of one to about four carbon atoms, 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkaxy moiety contains one to about four carbon atoms and the alkyl moiety,contains one to about four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R'I is a carbon-carbon bond R', and R, together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to about four carbon atoms;
RZ is selected from the group consisting 'of hydrogen, alkyl of one to about four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms;
or a pharmaceutically acceptable acid addition salt thereof.
However, tr.e inventic>n as claimed excludes the compounds of formula I wherein R1 is 1-<~lkynyl.
The invention also provides intermediate compounds of the formula N /''1 ~ NHCH.,R
R
wherein R is as defined above, Y is -NOp or -NH2, and R4 is alkoxyalkyl wherein the alkoxy moiety ccmta:ins one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms.
The invention further provides intermediate compounds of the formula WO 93/05042 ~CT/US92/07226 . ''~~~J 4 _ Cl N O
\NHC~i2RS
R
wherein Y and R are as defined above and RS is 2-, 3-, or 4-pyridyl.
This invention provides intermediate compounds of the formula N ~1 ~ / R2 N
CH~Rg R
wherein R, Ra, and ~ are as defined above.
This invention provides intermediate , compounds of the formula 0 0+ N
N~ ~ . _ °N
t ~~~ CH~Ra R , wherein R, Rz, and R~ are as defined above.
Further this invention provides compounds of the formula WO 93/05042 -t ~ r ; ~ < f PCT/US92107226 ~:~Z~ ~~~~~~
N N
' R2 N
j~~ CH2R5 R
wherein R, R2, and R5 are as defined above.
This invention also provides intermediate compounds of the formula N~ N
~ ~°° R 2 ~N
R
wherein R and R2 are as defined above and R6 is alkanoyloxyalkoxy methyl or aroyloxyalkoxy methyl wherein the alkyl group contains one to about four carbon atoms, or tetrahydrofuranyl st,abstituted by one or more substituents independently selected from the . group consisting of alkanoylo~cy, aroyloxy, and alkanoyloxyalkyl and aroyloxyalkyl wherein the alkyl group contains one to about four carbon atoms.
R1 of Formula I is preferably alkoxyalkyl or 4-pyridyl.
Other substituents in compounds of Formula I
that contain an alkyl radical (e. g., R when R is alkoxy or alkyl) preferably contain two carbon atoms or, more preferably, one,carbon atom in each alkyl radical.
It is preferred that R of Formula I be hydrogen.
Preferred compounds of Formula I include:
1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-.4-amine;
1-(2-propynyl)-iH-imidazo[4,5-c]quinolin-4-amine;
1-[(tetrahydro-2H-pyran-2-yl)methyl]-1H-imidazo[4,5-c]-quinolin-4-amine; and 1-(2-pyridylmethyl)-iH-imidazo-[4,5-c]quinolin-4-amine.
Most preferred compounds of Formula I
include 1-(2-methoxypropyl)-2-methyl-1H~-imidazo[4,5-c]quinolin-4-amine, 1-(2-methoxyethyl)-l-methyl-1H-imidazo[4,5-c]quinolin-4-amine and ~.-(4-pyridylmethyl)-iH-imidazo[4,5-c]-quinolin-4-amine.
Compounds of Formula I can be prepared by alkylating the 1-position of a 1H-imidazo[4,5-c]-quinolin-4-amine with an alkylating agent of the formula (R' ~ ) (R~ ) HC-X wherein R' ~ and R~ are as defined above and X is chloro or bromo, in a polar solvent in the presence of sodium hydride. In instances Wherein R, comprises a hydroxyl group, the hydroxyl group can be protected for the alkylation step and subsequently deprotected. Suitable protecting groups include alkanoyloxy (e. g., acetoxy) ar aroyloxy (e. g., benzoyloxy or p-toloyloxy). Reactions for placement and removal of such groups are well known to those skilled in the art and disclosed, e.g., in U.S. Pat.
No. 4,689,338 (Gerster), Examples 115-123. 1H-Imidazo-[4,5-c]quinolin-4-amines can be prepared as set forth in Scheme I below:
WO 93/0S042 fCT/US92/07226 ,.1 Scheme I
N02 'N02 NOz NO c~ N~~ c~ NO
OH Cl ~NHRE
R II
R III R IV
C3) sO~N N ~) N N ~) N NH2 ~R2 ~ ~R2 'N ~N
RE RE NHRE
R VII R VI R V
Id N~ t~ N N C~ N N
~R~ ~ ~R2 ~ ~R2 _N -~N N
RE RE H
R R R
VIII IX X
In Scheme I, R and R2 are as defined above and RE is a substituent capable of being subjected to an elimination or like reaction to afford a 1.H-imidazo-[4,5-c~quinolin-4-amine. R~ can be any substituent that can be removed. Examples of general classes of RE
include groups that will yield a stable ration upon -w treatment with aqueous acid (e.ga tertiary substituents, meaning for the purposes caf the instant specification and claims any substituent wherein the carbon atom bonded to the 1-nitrogen is fully substituted with electron-donating groups, for example hydroxy, alkoxy, acyloxy, halogen, alkyl, phenyl, and the like) and substituents from which the 1H-imidazo[4,5-c]quinolin-4-amine can be eliminated (e. g.
2-hydroxyalkyl groups). Such RE substituents include 1,1-dimethylethyl (i.e., t-butyl), l,l-dimethyl-2-hydroxyethyl, 2-hydroxy-i-phenyl-1-methylethyl, 1,1-dimethyl-2-hydroxypropyl, and the like.
Many quinolines of Formula III are known compounds (see, for example, U.S. Pat. No. 3,700,674 and references cited therein). Those that are not known can be prepared by known methods, for example, from 4-hydroxy-3-nitroquinolines as illustrated in step (1) of Scheme I. Step (1) can be conducted by reacting the 4-hydroxy-3-nitroquinoline of Formula II with 1-2 moles of phosphorus oxychloride per mole of the 4-hydroxy-3-nitroquinoline of Formula II. The reaction can be conducted in N,N-dimethylformamide and can be accompanied by heating. In step (2) a 3-nitro-4-chloroquinoline of Formula III is reacted by heating with a compound of the formula RENH2, wherein RE
is as defined above, in a suitable solvent such as dichloromethane, water, or tetrahydrofuran, and optionally in the presence of a tertiary amine catalyst such as triethylamine to provide a quinoline of Formula IV.
Steps (1) and (2) can be combined such that the 3-nitro-4-chloroquinoline need not be, isolated prior to reaction with RENH2. Such a reaction is exemplified in Example 134 and Example 188 (Step A) of U.S. Pat. 4,689,338.
A compound of Formula IV is reduced in step (3) preferably using a catalyst such as platinum on charcoal, to provide a campound of Formula V. The reduction can be carried out conveniently on a Paar apparatus in an inert solvent such as toluene or a lower alkanol.
In step (4) an intermediate compound of Formula V is reacted with (i) a 1,1-dialkoxyalkyl alkanoate such as diethoxymethyl acetate, or (ii) a WO 93!05042 ~" ~' '"1 ~~ ~~ 6'CT/US92/07226 _ g _ carboxylic acid that will introduce the desired RZ
group, or (iii) a trialkyl ortho ester of the formula R2C(Oalkyl)3, wherein "alkyl" is an alkyl group containing 1 to about 4 carbon atoms, or (iv) a combination of such a carboxylic acid with such a trialkyl ortho ester to provide a compound of Formula VI. The reaction can be carried out by heating, e.g., at about 130°C, in the presence of an acid, preferably an alkanoic acid having one more carbon atom than R2.
Step (5) provides an intermediate of Formula VII. First, the hydroxy group, if ane is present in RE, is protected with, for example, an alkanoyloxy group such as acetoxy, or with benzoyloxy. Such protecting groups and reactions for their placement and removal are well known to those skilled in the art. See, for example, U.S. Pat. No. 4,689,338, Examples 115 to 123.
The resulting protected compound is then oxidized with a conventional oxidizing agent that is capable of forming N-oxides. Suitable oxidizing agents include 2o peroxyacids and hydrogen peroxide. Heating is generally employed to accelerate the rate of reaction.
In stag (6) an N-Qxide of Formula VII is first heated in the presence of a suitable chlorinating agent such as phosphorus oxychloride to provide an intermediate of Formula VIII. Phosphorus oxychloride can be used in combination with a solvent (e. g., dichloromethane) inert to conventional chlorinating agents, optionally in the presence of a catalytic amount of N,N-dimetl~ylformamide. The second part of step (6) involves removal of the protecting group, if one is present, by methods well known to those skilled in the art.
In step (7) the 4-chloro group is replaced by a 4-amino group to provide a compound of Formula IX.
The intermediate of Formula VIII can be heated, e.g., at 125° to 175°C under pressure for 6-24 hours in a sealed reactor in the presence of either ammonium hydroxide or a solution of ammonia in an alkanol, WO 93105042 PCfI US92/07226 _ 10 _ (e.g., 15% ammonia in methanol). In step (8), a compound of Formula IX is heated in the presence of .
aqueous acid to effect the deamination of the RE group, thus providing a 1H-imidazo[4,5-c]- quinolin-4-amine of Formula X. Preferred conditions for the reaction include brief (e. g., 30 minute) reflux in dilute (e. g.
4N) aqueous hydrochloric acid.
Another method of preparing compounds of Formula I involves the reactions shown in Scheme II
below. , Scheme II
NOZ
_ NO
R III
Cz) -C'+ N NC
NO ~R ( 2 ) N 2 N
~NHCH R
rH2R1 2 1.
R XII R XI
(3) N N
~T
a .fR
I
Steg 1 of Scheme II involves reacting a .' campound of Formula III in an inert solvent with an amine of the formula R~CHzNH2 to provide a compound of W~ 93/05042 Formula XI. The reaction of step 1 can be carried out in the presence of a tertiary amine catalyst (such as triethylamine).
Step 2 involves: (i) reduction of the vitro group of the compound of Formula XI as described above in connection with step (3) of Scheme I; (ii) reaction of the resulting 3-amino compound with a carboxylic acid or an equivalent thereof as described above in connection with step (4) of Scheme I in order to provide a cyclized imidazo[4,5-c]quinoline; and (iii) oxidizing the quinoline nitrogen as described above in connection with step (5) of Scheme I to provide the -w N-oxide of Formula XII.
~1 1H-imidazo~4,5-c]quinolin-4-amine is prepared in step (3) of the Scheme II. Step (3) involves (i) reacting a compound of Formula XII with an acylating, agent; (ii) reacting the product with an aminating agent; and (iii) isolating the compound of Formula I. Part (i) of step (3) involves reacting an N-oxide with an acylating agent. Suitable acylating agents include alkyl- or aryl- sulfonyl chlorides ~(e.g., benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. p-Toluenesulfonyl chloride is most preferred. Part (ii) of step (3) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e. g., ammonium carbonate, ammonium bicarbonate, and ammonium phosphate). Ammonium hydroxide is preferred. The reaction of step (3) is preferably carried out by dissolving the N-oxide of Formula XII in an inert solvent such as methylene chloride, adding the aminating agent to the solution, and then adding the acylating agent. Preferred conditions involve cooling to about 0°C to about 5°C
during the addition of the acylating agent. Heating or . , , ... . . , . . . ... . . .. .. . ..
.. ~,. ..41.. , . A... , .u. .....1~: _......... .. . e..Va'.e.. v r.'~. . -yd_.. v r W . .aa s.- . ~.. , . . . ~ ~ . .. . , . . a . .
WO 93/05042 ~''~'~~'~a PCT/US92/07226 =~~'~-'~.~
cooling can be used to control the rate of the reaction.
Compounds of Formula XIX, a subgenus of Formula I, can be prepared according to the general method disclosed in U.S. Pat. No. 4,988,815 (Andre et .. ' al.), as shown below in Scheme III, wherein R and R2 are as defined above and R~ is 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, 2-, 3-, or 4-pyridyl.
a III . ~
O O NOa HN' (1~.~ N I ~2~ O
OH pH ~
R I~ R %~ R ~
r ~ Q 3~ ~
N ~ ,~~
N
I
~2~
R ~ R ~ R ~ ..
O _ ~~--R2 ( _____.. . ..____.__ ..._.~. ...... ..".. .., .,a"..~, . . .. , " :~.~. .~...
;_. .....;. .~.:,~:. ... ... , .~...,~ ~- .... . .. ~;.. _., , .~-. . . ... .
, .
13 _ The unsubstituted compound of Formula XIII, 4-hydroxy-2(iH)-quinolinone, is a known, commercially available compound, and other compounds of Formula XIII
can be prepared therefrom by methods known to those skilled in the art. For example, Chg;m. Ber., 1927,~6~, 1108 (Kohler), discloses the preparation of 7-chloro-4-hydroxy-2(1H)-quinolinone.
In step (1) a compound of Formula XIII is nitrated at the 3-position using conventional nitration methods. It is known to those skilled in the art, however, that nitration is not necessarily selective.
For example, depending on the particular ~t substituent in a compound of Formula XIII and the particular conditions employed, nitration might occur on the benzo ring of a compound of Formula XIII. Those skilled in the art, however, are able to select appropriate conditions that will afford a compound of Formula XIV.
Suitable conditions involve mild heating (e.g., at about 40°C) with acetic acid as the solvent. The unsubstituted compound of Formula XIV, 4-hydroxy-3-nitro-2(1H)quinoline is known and the preparation thereof is disclosed in Chem. B_er_._, 1918, -5~.~ 1500 (Gabriel) .
In step (2) the nitrated compound of Formula XIV is chlorinated with a suitable chlorinating agent such as phosphorus pentachloride or phosphorus oxychloride to provide the dichloride product of Formula XV. The reaction can be carried out in an inert solvent or if appropriate in neat chlorinating agent. Mild heating serves to accelerate the rate of reaction. The unsubstituted compound of Formula XV, 2,4-chloro-3-nitroquinoline, is known and the preparation thereof is disclosed in Gabriel cited above.
The product of Formula XV can be isolated if desired, but steps (2) and (3) can be carried out without isolation of the compound of Formula XV. Such I~VO 93/05042 PC~'/US92/07226 - ~4 a process involves carrying out the reaction of step (2), careful hydrolysis of unreacted chlorinating agent at a relatively low temperature (e. g., below about 35°C), separating the organic layer, removing the product of Formula XV from the remaining aqueous layer by extraction with an organic solvent, and using the combined organic extracts as described below in connection with step (3).
In step (3), a compound of Formula XV is substituted at the 4-position by reaction with an excess of a compound of the formula RyCH2NH2, wherein R., is as defined above. It is sometimes necessary to use gentle heating (e. g., 50°C). This reaction proceeds selectively, affording only the~4-substituted product and no detectable amount of the 2-substituted compound.
The reaction is run in a solvent comprising a base such as triethylamine or pyridine. When step (3) is run independent of step (2), the reaction can be carried out in a neat basic solvent such as triethylamine.
Gentle heating (e. g., at about 70°C) is preferred.
In step (4), a compound of Formula XVI is reduced to afford a compound of Formula XVII. This reduction can be carried out by conventional methods such as by electrochemical reduction, by reaction with metals such as zinc, tin, or iron in acid, and by other conventional single step or multi-step methods known to thane skilled in the art. Suitable reduction conditions include conventional homogeneous or preferably heterogeneous catalytic hydrogenation conditions. A compound of Formula %VI is suspended or dissolved in a solvent such as ethanol, ethyl acetate, methanol, isopropyl alcohol, or mixtures thereof with acetic acid, in the presence of a suitable heterogeneous hydrogenation catalyst such as a platinum or rhodium on alumina, palladium on carbon, platinum on carbon, or the like under hydrogen pressure (e.g., 1-5 atm) in a steel bomb. Isopropyl alcohol is the preferred solvent.
WO 93/0j042 ~ '~ ~ ~ r~ ~~ F~ PCT/U592/07226 In step (5), a compound of Formula XVII is reacted with an orthoester or an orthoformate of the formula RZC (O-Alkyl) 3 or a carboxylic acid of the formula R2COZH or a mixture thereof, as described above in connection with step (4) of Scheme I.
In step (6), a compound of Formula XVIII is reacted with ammonia as described above in connection with step (7) of Scheme I to afford a compound of Formula XIX.
Compounds of Formula I can be isolated by the conventional means disclosed in U.S. Pat. No.
4,689,338 (Gerster), such as, for example, removal of the solvent and recrystallization from an appropriate solvent (e. g., N,N-dimethylformamide),or solvent mixture, or by dissolution in an appropriate solvent (such as methanol) and re-precipitation by addition of a second solvent in which the compound is insoluble.
A compound of Formula I can be used as an antiviral agent itself or it can be used in the form of a pharmaceutically acceptable acid-addition salt such as a hydrochloride, dihydrogen sulfate, trihydrogen phosphate, hydrogen nitrate, methar:.esulfonate or a salt of another pharmaceutically acceptable acid.
pharmaceutically acceptable acid-addition salt of a compound of Formula I can be prepared, generally by reaction of the compound with an equimolar amount of a relatively strong acid, preferably an inorganic acid such as hydrochloric, sulfuric, or phosphoric acid, or an organic acid such as methanesulfonic acid, in a polar solvent. Isolation of the salt is facilitated by the addition of a solvent, such as diethyl ether, in which the salt is insoluble.
A compound of the invention can be formulated for the various routes of administration in a pharmaceutically acceptable vehicle, such as water or polyethylene glycol, along with suitable adjuvants, excigients, and the like. Particular formulations will be easily selected by those skilled in the art.
dV0 93/05042 PCT/US92/07226 15 ~-Suitable formulations for topical application include creams, ointments and like formulations known to those skilled in the art. Formulations generally contain less than 10% by weight of a compound of Formula I, preferably about 0.1% to 5% by weight of a compound of Formula I.
The compounds of Formula I exhibit antiviral activity in mammals. They can therefore be used to control viral infections. For example, a compound of Formula I can be used as an agent to control infections in mammals caused by Type IT Herpes simplex virus.
Compounds of Formula I can also be used to treat a herpes infection by oral, topical, or intraperitoneal administration.
A number of compounds of Formula I were tested and found to induce biosynthesis of interferon in human_cells. The test methods and results are set forth below. These results suggest that at least certain compounds ~f the invention might be useful in treating ~ther diseases such as rheumatoid arthritis, warts, eczema, Hepatitis H, psoriasis, multiple rsclerosis, essential thrombocythemia, cancer such as basal cell carcinoma, and other neoplastic diseases.
In the following Examples, alI reactions were run with stirring under an atmosphere.of dry nitrogen unless otherwise indicated. The particular materials and amounts thereof recited in the Example, as well as other conditions and details, should not be construed to unduly limit the invention.
Example 1 1-Eth eth -1 -i 'dazo 5-c uin lin-4-amin A 0.48 g (0.012 mole) portion of 60% sodium hydride was added to a suspension of 2.0 g (0.011 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 20 mL of dimethylformamide. The resulting mixture was stirred for about 45 minutes until a solution was obtained. A
1.07 g (0.011 mole) portion of chloromethyl ethyl ether WO 93/05042 ~ ~ ,f ~~ PCl'/US92/07226 a,.
- i~ -was added to the solution. A precipitate formed immediately. The reaction mixture was stirred at room temperature for one hour. The precipitate was collected, slurried with water then dried to give 1.4 g of a solid which was identified as the 1-isomer by nuclear magnetic resonance spectroscopy. This solid was recrystallized from 150 mL of ethanol to provide 0.86 g of 1-ethoxymethyl-iH-imidazo[4,5-c]quinolin-4-amine, m.p. 255-261°C. Analysis: Calculated for C~3H~4N~0: %C, 64.4; %H, 5.8; %N, 23.1; Found: %C, 64.2;
%H 5.8, %N 22.8.
Example 2 ~-(2-Progy,~,~y~y-1H-imidazo[4:5-clcuinolin-4-amine Using the general method of Example 1, 2.1 g of iH-imidazo[4,5-c]quinolin-4-amine was reacted with 1.7 g of propargyl bromide to provide 0.4 g of 1-(2-propynyl)-1Ii-imidazo[4,5-c]quinolin-4-amine, m.p.
220-222°C. The structure was confirmed by nuclear magnetic resonance spectroscopy. Analysis: Calculated for Cl3H~oN4: %C, 70.3; %H, 4.5; %N, 25.2; Found: %C, 70.5; %H, 4.6; %N, 25.4.
n ..y'.
Example 3 1- f (Tetrahydro-2H-pyran-2 yly met~yrl ] -~H-imidazoj4 5-c]q ;no~.ip-4-amine, Using the general method of Example 1, 3.0 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with 2-bromomethyltetrahydropyran to provide about 2.5 g of a mixture of the 1 and 3 isomers. The mixture was slurried with about 30 mL of refluxing ethyl acetate then, cooled in, an, ice. bath. The resulting precipitate was collected and dried to provide 0.6 g of 1-[(tetrahydro-2H-pyran-2-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 206-210°C. The structure was confirmed by nuclear magnetic resonance spectroscopy . Analysis : Calculated f or C~6H1aN40: %C, _ _ _ __-._._r.___....,___.,...,_,..~..~.....,.,.,.a,. ~.- .._ . ,. T-ee.,,.~a..ea-rra.".c . .,..,z,~r~.. ~;.r,W ~<!s~rtT..~ . ,.
v,T.,dfl~.~,.6Y~,S~: . '.'T,T:V':::; .v.k'.,",H."'\a , ,.,.,'i:..1,~1.~... , ':.. , ... . . . .
r. f V4'O 93/05042 C~~ y ~- '~ PCT/ US92/07226 _ 18 _ 68.1; ~H, 6.4; ~N, 19.8; Found: ~C, 67.8; %H, 6.4; ~N, .
19.6. .
Example 4 1-Ll2-Acetoxyethoxv~meth~,l,]-iH-imidazo~ 4.5-clquinolin-4-amine Using the general method of Example 1, 5.0 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with (2-acetoxyethoxy)methyl bromide (prepared according to the method of Robins et al., Can. J. C,em. C0, 547 (1982)) to provide 5.3 g of a yellow solid. The solid was slurried with ethyl acetate to provide 2.3 g oa: a light yellow solid which was identified as the 1-isomer by nuclear magnetic resonance spectroscopy.
Example 5 1° C ~Ydro~ethaxv met 1,] -iH-in~ic~azo j 4,, 5-c Lg~ on lin-g-~~,i~n~
A 2.1 g portion of 1-[(2-acetoxyethoxy)-methyl]-iH-imidazo[4,5-c]quinolin-4-amine was combined with 25 mL of 15~ ammonia in methanol and stirred at room temperature fc~r about 16 hours. The resulting precipitate was collected, rinsed with ether and dried to provide 1.1 g of a solid. This solid was recrystallized from 50 mh of ethanol to provide 0.8 g of 1-[(2-hydroxyethoxy)]methyl-iH-imidazo[4,5- .
c]quinolin-4-amine as a yellow crystalline solid, m.p.
210-212°C. Analysis: Calculated for C'3H'$N4o2: ~C, 60.4; ~H, 5.5; %N, 21.7; FOUnd: ~C, 60.3; ~H, 5.5, %IJ, 21.5.
Example 6 1-(2-Deoxy-3.5-di-O-p-toluoy~-D-esythro pentofuranosyl) -1H-~midazo [4 45-c~quinolin-4-amine A 0.34 g (0.011 mole) portion of 60% sodium hydride was added to a suspension of 1.7 g (0.009 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 65 mL of methylene chloride. The reaction mixture was then .
diluted with 65 mL of acetonitrile and stirred at room temperature for 2 hours. 3.6 g (0.009 mole) of 2-deoxy-3,5-di-O-p-toluoyl-D-erythropentosyl chloride (prepared according to the method of Bhat, pp. 521-22 from Volume 1, Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson (1968)) was added to the reaction mixture and stirring at room temperature was continued for about 16 hours. The reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was evaporated to provide a residue which was purified by silica gel chromatography using ethyl acetate as the eluent to provide 1.4 g of the 3-isomer and 2.0 g of the 1-isomer. The structural assignments were confirmed by nuclear magnetic resonance spectroscopy.
Example 7 1- l2-Deoxv-B-D-ego _pentofuranosvl ) -~H-imidazo[4.5-clguinolin-4-amine A 2.2 g portion of 1-(2-deoxy-3,5-di-O-p-toluoyl-D-erythro-pentofuranosyl)-1H-imidazo[4,5-c]-quinolin-4-amine was dissolved in about 150 mL of 15%
ammonia in methanol and stirred at room temperature for about 48 hours. The volume of the reaction was reduced to about 50 mL and the precipitate collected to provide 0.56 g of a solid. The filtrate was evaporated and the residue was slurried with ether then ffiltered to provide 0.55 g of a solid. The two solids were combined then recrystallized from ethanol to provide 0.8 g of 1-(2-deoxy-~-D-erythro-pentofuranosyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 232-237°C.
Analysis: Calculated for CHSHt6N4O3: %C, 60.0; %H, 5.4;
%N, 18.7; Found: %C, 59.7; %H, 5.4; %N, 18.3.
Example 8 N-(2-Methoxvethyl)-3-vitro-4-guinolinamine A mixture containing 16 mL (0.22 mole) of thionyl chloride and 18 mL of dimethylformamide was ," , Z.~..., . w~ .:. ~. .
'5'.a .,c'i1~1,.~. ,..::.'".,):,:, :' 1, . ..;..4,., 'i 1 ~.
r.,.t .1 ~G. r rn.~ ' .,a ",. v?,. 4: ~a ' a .
. n:.~: .. . ~. r. ,' " ~.- . ~ .. a~ ~:-tt . . ,~. ~1~ ,, "_~.
~. n ...~,. . ya , ,....,R
. a..,a ' ~ . .v , rt w. , q ..
u'~S!. . .'t,. . 1~ . ~:
A.
...:fS .. c. h. ,.: ~.~ ~. , ~, . ct.,.; iY
..f.:.
.~...m~fa. .., ~ x. t "4. ,., " ..> ~_ 1: ., ~~~ . , q~,.. '< , a ,. . ~, ..,.
, n . i' a ~, , ru:~ ~..w , .:4':,t ...\. vt,... ~f c 'fit. b ~. » ' ~ t . .;Y ..~.. Z.~..
\ .
5.
.1 ! ~. ~'~.
.~. . . -;~. ., ..
.. . .. . , ., . . . ..a 5~ . . .~.. , .Z..,..2:~:...,. ,. . . ... 5.. .ri: s'G4f'nara.Zt..w. ,..»,...u.t....
.C~;,~:e,i. .,~,.~.:1.
al....'l...a~,.,a~~.tva....e.Jti'!.'2,.,.5.~~~~.e,~.."a:K, .
a.~.:.~~2~..~.w..~1."... a.~..~." _y._ ..tA.,-.. .$'r.... v .
V1!O 93/05042 PCT/US92/07226 t) 2 0 added to a suspension of 38 g (0.2 moles) of 4-hydroxy-3-nitroquinoline in 500 mL of dichloromethane. The resulting mixture was heated at reflux for 2 hours and then allowed to cool to room temperature. A 20 mL (0.23 mole) portion of methoxyethylamine was combined with 30 mL of triethylamine and the combination was slowly added with vigorous stirring to the reaction mixture. A vigorous heat of reaction was observed and the mixture was allowed to reflux until the heat of reaction dissipated. The reaction mixture was concentrated under vacuum to provide a residue which was then slurried with dilute hydrochloric acid. The slurry was filtered and the filtrate was made basic with ammonium hydroxide. The resulting precipitate was collected, rinsed with water and air dried to provide 37.4 g of a yellow solid. A sample of this material was recrystallized from ethanol-dichloromethane to provide N-(2-methoxyethyl)-3-nitro-4-quinolinamine as a yellow solid,' m.p. 113-115°C. Analysis: Calculated for Cl~i~3N3O3: %C, 58.3; %H, 5.3; %N, 17.0; Found: %C, 58.0;
%~i, 5.3; %N, 16.8.
Example 9 1-- (~-Methoxyethyl ) -2-methyl-7iH-imidazoj 4 . 5-c,~quinoline A mixture containing 12.5 g of N-(2-methoxyethyl)-3-nitro-4-quinolinamine, 0.6 g of 5%
platinum on carbon, 10 g of magnesium sulfate and 380 mh of ethyl acetate was hydrogenated in a Parr apparatus at an initial pressure of about 53 psi.
After the hydrogenation was complete, the reaction mixture was filtered. The filtrate was evaporated, under vacuum to provide the diamine intermediate as a clear amber oil. The oil was taken up in 150 mL of glacial acetic acid and the resulting solution was refluxed for one and a half hours before being evaporated under vacuum. The resulting residue was dissolved in water. The solution was made strongly 'I~VO 93/05042 P~1'/US92/07226 ~i.~ ~'~~'~
f F.~
basic with aqueous sodium hydroxide then extracted several times with ethyl acetate. The extracts were combined, dried over magnesium sulfate and evaporated.
The residue was slurried with ether/hexane then filtered to provide 9.5 g of crude product. A 0.5 g sample was recrystallized to provide pure 1-(2-methoxyethyl)-2-methyl-1H-imidazo[4,5-c]quinoline, m.p. 128-130°C. Analysis: Calculated for C,4H95N3o: %C, 69.7, %H, 6.3; %N, 17.4; Found: %C, 69.8j %H, 6.3, %N, 17.4.
Example 10 1- ( 2-~tethoxyet ~y~~ -2-methy -1H-imidazoj4 5-c,]quinol~n-4-amine I5 A 6.3 mL (0.03 male) portion of 32%
peracetic acid was added to a solution of 7.0 g (0.029 mole) of_1-(2-methoxyethyl)-2-methyl-iH-imidazo[4,5-c]quinoline in 100 mL of ethyl acetate.
The solution was heated at reflex for 30 minutes and then allowed to cool to room temperature. The resulting precipitate was collected, rinsed with a ..
small amount of ethyl acetate and dried to provide 7.7 g of the N-oxide as a solid. The N-oxide was dissolved in 125 mL of dichloromethane then mixed with 40 mL of concentrated ammonium hydroxide. The resulting heterogeneous mixture was stirred vigorously and cooled to 4°C. A 5.7 g (0.03 mole) portion of p-toluenesulfonyl chloride was dissolved in 25 mL, of dichloromethane and added dropwise to the mixture. The rate of addition was controlled such that the reaction mixture was maintained at a temperature of 4-9°C.
After the addition was completed the reaction mixture was allowed to stir at room temperature for one hour.
The dichloromethane was removed under vacuum. The w aqueous mixture was diluted further with water and the solid was collected, washed with water and dried to provide 6.1 g of crude product as a tan solid. The tan solid was recrystallized from methanol/dichloromethane W~ 93/05042 PCd'/~JS9210722b _ to provide 3.0 g of 1-(2-methaxyethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a colorless crystalline solid, m.p. 230-233°C. Analysis:
Calculated for C~4H16N4~~ %C, 65. fi; %H, 6.3; %N, 21.9;
Found: %C, 65.5; %H, 6.1; %N, 21.7.
Example 11 2-Chloro-3-vitro-N-°~2 gvrid~lmeth~,l)-4-auinolinamine A 8.2 g portion of 2,4-dichloro-3-nitroquinoline was dissolved in 85 mL of dimethylformamide. 2-(Aminomethyl)pyridine (2.5 mL) was added dropwise followed by the addition of 4.7 mh of triethylamine. The reaction mixture was stirred for minutes then an additional 1.0 mL.of 15 2-(aminomethyl)pyridine was added. The reaction mixture was stirred at room temperature for about an hour and then on a steam bath for about 45 minutes. -The reaction mixture was diluted with 1.50 mL of water.
The resulting precipitate was collected and dried to provide 7.3 g of a yellow brown solid. The solid was _slurried with about 75 mL of refluxing hexane then filtered while hot to give 4.5 g of a solid. A 200 mg sample was recrystallized from about 15 mh of ethanol to provide pure 2-chloro-3-vitro~N-(2-pyridylmethyl)-4-quinolinamine, m.p. 179-182°C. Analysis: Calculated fOr C~5C1H"N40~: %C, 57.2; %H, 3.5; %N, 17.8; FAUnd: %C, 57 . 4 ; %H, 3 . 6; %N, 17 0 7 s Example 12 2-Chloro-N4-(2-p~rid,~~lmethyl -3.4-~ainoline famine A mixture containing 5.8 g of 2-chloro-3-nitro~-N-(2-pyridylmethyl)-4-quinolinamine, 5.8 g of magnesium sulfate, 0:~ g of 5% platinum on carbon and 300 mL of ethyl acetate was hydrogenated on a Parr apparatus. After the hydrogenation was complete, the reaction mixture was filtered and the filtrate evaporated to provide 4.6 g of a solid. A sample was recrystallized from ethyl acetate/hexane to provide WO 93/USfl42 PCT/US92/07226 2~.~~'~'~~~
pure 2-chloro-N4-(2-pyridylmethyl)-3,4-quinolinediamine m.p. 98-102°C. Analysis: Calculated for C~SC1H13N4: %C, 63.3; %H, 4.6; %N, 19.7; Found %C, 63.5; %H, 4.7; %N, 19.8.
Example 13 4-Chloro-1-(~py~idylmethyl)-1H-imidazo_~'4 5-c~sruinoline A 1.6 mL portion diethoxymethyl acetate was added to a solution of 2.3 g of 4-Chloro-N~-(2-pyridyl-methyl)-3,4-quinolinediamine in 15 mL of warm xylene.
'the reaction mixture was heated on a steam bath for 90 minutes then diluted with hexane. The precipitate was collected and dried to provide 2.3 g.of a solid: A 300 mg sample was recrystallized from 10 mL of ethanol to provide pure 4-chloro-1-(2-pyridylmethylD-lI~-imidazo[4,5-caquinoline, m.p. 217-220°C. Analysis:
Calculated for C~gCIHi~Ndr %C, 65.2; %H, 3.8; %N, 3,9.0;
FOUnd: %C, 65.0; %H, 3.7; %N, 1$.8.
Example 14 1- 2- me H- 'd z 4 5- u' o 'ne A mixture of 2.4 g of 4-chloro-1-(2-pyridyl-methyl)-iH-imidazo[4,5-caquinoline and 50 mL of 15%
ammonia in methanol was placed in a bomb and heated at 150°C for 6 hours. After cooling, t:he reaction mixture was filtered. The solid was slurried with aqueous sodium bicar3aonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278-284°C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275-281°C. The two crops were combined for analysis. Analysis: Calculated for Ca6H~~Ns:
%C, 69.8; %H, 4.8; %N, 25.4; FOUnd %C, 69.7; %N, 4.8;
%N, 25.2.
WO 93/05042 PCT/US92/0?226 c,, r, .~ r~ ~ Ou.. i...:
Example 15 2-Chloro-3-vitro-N- ( 4-pvridvlmethvl ) -4-auinolinamine Using the general method of Example 11, 6.8 g of 2,4-dichloro-3-nitroquinoline was reacted with 4-(aminomethyl)pyridine to provide 7.8 g of crude 2-chloro-3-vitro-N-(4-pyridylmethyl)-4-quinolinamine.
This material was used without further purification.
Example 16 2-Chloro-N°-(4-pyridylmethvl -3.4-quinolinediamine Using the general method of Example 12, 5.0 g of 2-chloro-3-vitro-N-(4-pyridylmethyl)-4-quinolinamine was hydrogenated to provide 2.9 g of crude 2-chloro-N4-(4-pyridylmethyl)-3,4-quinoline-diamine. This material was used without further purification.
Example 1~
4-Chloro-1-(4-pyridylmethyl~-1H-imidazo 4.5-c~guinoline " A mixture containing 2.9 g of 2-chloro-N4-(4-pyridylmethyl)-3,4-guinolinediamine and 3 mL of diethoxymethyl acetate was heated on a steam bath for about 45 minutes. The reaction suspension was dissolved in cold dilute aqueous hydrochloric acid.
The solution was made basic with ammonium hydroxide.
The resulting oily solid was taken up in ethyl acetate and purified by silica gel chromatography using first ethyl acetate then 5% methanol in ethyl acetate as the eluent to provide 0.9 g of a solid. A 100 mg portion was recrystalli2ed from 5 mL of ethanol to provide 4-chloro-1-(4-pyridylmethyl)-1H-imidazo[4,5-c]-quinoline, m.p. >300°C. Analysis: Calculated for C16C1H~IN4: %C, 65.2, %H, 3.8, %N, 19.0; Found: %C, 64.8;
%H, 3.9; %N, 18.5.
WO 93/05042 PCT'/US92/07226 Example 18 1-(4-Pyridylmethvl)-1H-imidazo[4r5-clauinolin-4-amine Using the general method of Example 14, 0,8 g of 4-chloro-1-(4-pyridylmethyl)-1H-imidazo[4,5-c]quinoline was aminated to provide 0.25 g of 1-(4-pyridylmethyl)-iH-imidazo[4,5-c]quinolin-4-amine, m.p. >300°C. Analysis: Calculated for Cl6HisNs~ %C, 69.8;
%H, 4.8; %N, 25.4; Found: %C, 70.2; %H, 4.9; %N, 25.5.
Example 19 Part A
1- [ ( 3-Nitro-4 guinol inyl,~ amino, -2-propanol A mixture containing 16 mL (0.22 mole) of thionyl chloride in 18 mL of dimethylformamide was added with stirring to a suspension of 38 g (0.2 mole) of 9~-hydroxy-3-nitroquinoline. The resulting mixture was heated at reflux for 3 hours then cooled to -15°C
in a dry ace bath. A solution containing 18 mL (0.23 mole) of 1-amino-2-propanol and 30 mL (0.23 mole) triethylamine in 100 mL of methylene chloride was added dropwise with vigorous stirring to the chilled reaction mixture. After the addition was complete, the reaction mixture was heated at reflux for about 30 minutes. The reaction mixture was concentrated under vacuum to provide a yellow precipitate which was collected, rinsed with water and a small amount of ethanol and dried to provide 45 g of a yellow crystalline salid. A
1 g portion was recrystallized to provide 1-[(3-vitro- y 4-quinolinyl)amino]-2-propanol as a yellow crystalline solid, m.p. 209-210°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Part B
a,2-Dimethyl-iH-imidazol~4,5-c]quinoline-1--ethanol Using the general method of Example 9, 44.2 g of 1-[(3-vitro-4-quinnlinyl)amino]-2-propanol was hydrogenated to provide the intermediate diamine as a brown oil. Using the general method of Example 9, :», , .,. ~ . ,:;~ ,...
S" ~~'t . \.v.:'. v;.' .S . , . . .. r .... . . , ... . .,......, '..11'S~. ..mm.. ... . , ,.,. ~,:.~t , ..
"......,.. .,.. . ,..:i~.~,.. .. :,~..W ..... ....,.. ".v...:~.5~.,.....". a WO 93/05042 ,~~~D~~U.4~ PCT/U592/07226 17 g of the crude diamine was reacted with glacial acetic acid to provide 6.3 g of crude product. A
sample was recrystallized from ether to provide a,2-dimethyl-iH-imidazo[4,5-c]quinoline-1-ethanol as a blue tinged solid, m.p. 176-177°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Part C-1-l2-Methoxyprogyl)-2-methyl-iH-imidazoj4,5-c~guinoline Sodium hydride (1 g of 60%) was added to a suspension of 5 g (0.021 mole) of a,2-dimethyl-iH-imidazo[4,5-c]quinoline-1-ethanol in 100 mL of tetrahydrofuran. The resulting mixture was stirred for an hour. Methyl iodide (1.55 mL; 0.025 mole) was added and the reaction mixture was stirred for an hour. The reaction mixture was diluted with water then extracted three times with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of crude product as a brown oil. The oil was refluxed for one hour with 250 mL of hexane then filtered. The filtrate was cooled and the resulting precipitate was collected and dried to provide 2.4 g of a sticky light yellow powder. A sample was recrystallized from ether to provide 1-(2-methoxypropyl)-2-methyl-iH-imidazo[4,5-c]quinoline as a white crystalline solid, m.p. 55-57°C. ."
The structure was confirmed by nuclear magnetic resonance spectroscopy.
Example 20 1-(2-Methoxypro~vlf,]-2-methyl-1H-imidazo~4.5-clquinoline 5N ~~Cide Using the general method of Example 10, 2.4 g of 1-(2-methoxypropyl)-2-methyl-1H-imidazo[4,5-c]quinoline was oxidized using peracetic acid to provide 2.65 g of the crude N oxide as a yellow solid.
A 100 mg sample was recrystallized from ethyl acetate to provide d,-(2-methoxypropyl)-2-methyl-iH-imidazo[4,5-WU 93/05042 '" ~ ~ PCT/US92/07226 ~ ~. ; ~ '~ c.'. f c]quinoline 5N oxide as a solid, m.p. 146-149°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Example 21 1- ~( 2-Methoxy~rogvl) -2-methyl ~~.Fi-~midazo j 4 . 5-cl ino~,in-4-am,~;ne Using the general method of Example 10, 2.55 g of 1-(2-methoxypropyl)-2-methyl-1H-imida~o[4,5-c]quinoline 5N oxide was aminated to provide 2.5 g of crude product as a light orange powder. The powder was recrystallized from ethyl acetate to provide 1.46 g of 1-(2-methoxypropyl)-2-methyl-iH-imida~o[4,5-c]quinolin-4-amine as a white crystalline solid,.m.p. 196-197'°C.
Analysis: Calculated for C~~H~8N40: %C, 66.6; %H, 6>?; %N, 20.7; Found: %C, 66.4; %H, 6.7; %N, 20.6.
Compounds of the invention were tested according to the test methods set forth below.
ANTIVIRA7L ACTIVITS~ AND
INTERFERON INDUCTION IN GUINEA hIGS
The test methods described below demonstrate the ability of compounds of the invention to xeduce the number and severity of lesions developed by guinea pigs infected with Type II Herpes simple5c virus and to induce the biosynthesis of interferon in guinea pigs.
Female Hartley guinea pigs weighing 200 to 250 g are anesthetized with methoxyflurane (available under the tradename METAFANET~'' from Fitman-Moore, Inc., Washington Crossing, NJ), after which the vaginal area is swabbed with a dry cotton swab. The guinea pigs are then infected intravaginally with a cotton swab saturated with Herpes simplex virus Type II strain 333 (1 X 10S plaque forming units/mL). Guinea pigs are assigned to groups of 7 animals; one group for each treatment and one to serve as a control (vehicle treated). The compounds of the invention are a n Cta:. r t/ y ~.'~~ - 2 8 -formulated in water containing 5% Tween 80 (a polyoxyethylene sorbitan monooleate available from Aldrich Chemical Company, Inc., Milwaukee, WI). The guinea pigs are treated orally once daily for four consecutive days starting 24 hours after infection.
Antivi~al Activitv Antiviral activity is evaluated by comparing lesion development in compound-treated versus vehicle-treated guinea pigs. External lesions are scored 4, 7, 8 and 9 days after infection using the following scale:
0 - no lesion, 1 - redness and swelling, 2 - a few small vesicles, 3 - several large vesicles, 4 - large ulcers with necrosis and 5 - paralysis. The maximum lesion score of each guinea pig is used to calculate the percentage lesion inhibition. The percentage lesion inhibition is calculated as follower Sum of maximum lesion scoops of treatment group x 100 100- Sum of maximum lesion scores of control group Inte,~feron Induction Twenty-four hours after the initial dose of test compound has been administered, blood is obtained from 3 guinea pigs from each treatment group by cardiac puncture of methoxyflurane anesthetized animals. Flood is pooled and allowed to clot at room temperature.
After low speed centrifugation, serum is collected and stored at -70°C until analysis.
Interferon levels in the guinea pig serum are determined in a standard microtiter essay using transformed guinea pig cells (ATCC CRL 1405). The interferon assay is done in 96 well microtiter plates.
Confluent monolayers of transformed guinea pig cells are treated with dilutions of guinea pig serum made with medium 199 (GIBCO, Grand Island, NY). The cell and serum dilutions are incubated at 37°C overnight.
-, ., . ___. . r . , . . . . . . . . . ...> ..~m .. . ~ .. , , . _...,.,... ,. . :,.~t..,.,:. ...". ."..,..,,... :.. ... ..
._u..,_... ~~ ..
WO 93/05042 ~ ~ 1 ~ ~ ~ t' PCT/US92/07226 The following day, the medium and serum are removed and about 10 plaque forming units of Mengavirus are added to each well. Controls consist of wells that receive no guinea pig serum (virus positive control) and wells that receive no virus (virus negative control). Cells and virus are incubated for 2 to 3 days at 37°C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining with 0.05%
crystal violet followed by spectrophotometric absorbance measurements. The titer of interferon in serum is expressed as units/mL and is the reciprocal of the highest dilution that protects cells from virus.
Results are shown in the table below.
Antiviral Activity and Interferon Induction in Guinea Pigs 2o Compound of Dose % Lesion Reference example ~na/ka inhibition Units,fmL
1 2 55% not determined 2 2 5?% 600 14 2 20% not determined i8 2 0% not determined 18 5 88% a12,800 These results show that the tested compounds of the invention inhibit Herpes simplex virus type IT lesions in guinea pigs. Those compounds tested were also shown to induce interferon biosynthesis in guinea pigs.
WO 93/t~5042 PCT/US92/07226 cr; '~ ,;, INTERFERON-a INDUCTION IN HUMAN CELLS
The test methods described below demonstrate the ability of compounds of the invention to induce the biosynthesis of interferon-a in human cells.
An in vitro human blood cell system was used .
to assess interferon-a induction by compounds of the invention. Activity is based on the measurement of interferon secreted into culture medium. Interferon is measured by bioassay.
Blood Cell Preparation for Cu,~ture Whole blood is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBM's) are prepared by LeucoPREPT~'' Brand Cell Separation Tubes (available from Becton Dickinson) and cultured in RPMI 1640 medium (available from GIBCO, Grand Island, NY) containing 25 mM HEPES
4-(2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid and v-glutamine (1% penicillin-streptomycin solution added) with 10% autologous serum added. Alternatively, whole blood diluted 1:10 with RPMI 1640 medium supplemented with 25 mM HEPES and L-glutamine with 1%
penicillin-streptomycin solution added can be used.
200 ~ch portions Qf diluted whole blood or of PBM in medium are added to 96 well (flat bottom) MicroTest'~"III
tissue culture plates.
Compound Preparation The compounds are solubilized in water, ethanol, or dimethyl sulfoxide then diluted with dist~.lled water, 0.01N sodium hydroxide or 0.01N
hydrochloric acid. (The choice of solvent will depend on the chemical characteristics of the compound being tested.) ._ ~1 _ Incubation The solution of test compound is added (in a volume less than or equal to 50 ~L) to the wells containing 200 ~.L of PBM in medium or diluted whole blood. Solvent and/ar medium is added to control wells (i.e., wells with no test compound) and also as needed to adjust the final volume of each well to 250 uL. The plates are covered with plastic lids, vortexed gently and then incubated for 24 hours at 37°C with a 5%
carbon dioxide atmosphere.
Separation Following incubation, the plates are covered with PARAFILM~ and then centrifuged at 1000 rpm for 15 minutes at 4°C in a Damon IEC Model CRU-5000 centrifuge. Medium (about 175 ~L) is removed from 4 to 8 wells and pooled into 2 mL sterile freezing vials.
samples are maintained at -70°C until analysis.
Interferon Analysis Calculation Interferon i~; determined by bioassay using A549 human lung carcinoma cell chal.leng=>d with encephalo myocarditis. The details of the bioas:>ay method are described by G. L. Brerlnan and L. H. Kronenberg in "Automated Bioassay of Int:erferons in Micro-test Plates", Biotechniques, June/,Ju:Ly; 78, 195:3. Briefly stated the method is as follows: intEerferon di.l_utions and A549 cells are incubated at 37°c' ror 1.'<? t:o ~'4 I~~ours. The incubated cells are infected with an inoculum of encepha:Lomyocarditis virus. The infected cells are incubated for an additional period at 37 °C; before quant:i.f yind fc>r viral cytopathic effect. The viral cytopathic effect is quantified by staining followed b~~ spectrophot<arnetric absorbance - 31a -measurements. Results a.re expressed as a interferon reference units/mL based on the value obtained for NIH HU
IF-L standard. The interferon was identified as essentially W~O 93/05042 PCT/US92/07226 y ~' A
all interferon alpha by testing in checkerboard neutralization assays against rabbit anti-human interferon (beta) and goat anti-human interferon (alpha) using A549 cell monolayers challenged with encephalomyocarditis virus. Results are shown in the table below wherein the absence of an entry indicates that the compound was not tested at the particular dose concentration. Results designated as "~~~ a certain number indicate that interferon was not detectable in amounts above the lower sensitivity level of the assay.
wo 93iosoa2 w" ~ i ~t ~ ~° Sv ~~ Pcrius9zio~za~, J F,l d O
O p ~ W ~ ~ W
U ~
~ ~ ~
~ o 0 y c * * vv *
M r-d r-i t~ O e~ ,~ ct er O O C7O
"
r1 t e-1~p Ca tp Q~ M f~r1 li~ 1 r~i ' ' 1~
ey d ,d'h tn O fa * ~ * * * * * *
N r1 r x ~
0 0 ~co o o a ~-1 N * * ~ ~1 h c~1M
Q ~ ~ '~ V ~' m c~co , ..-i ~!
+~ ~ w ~ G ~ ~ ~
~ ~ p ,..~0 0 * *
N H v ' O V a-~ '~~
H G~IC
4.aO
O
pp * * * * v V M v O
%.a ~
* * * * * ~' ~ rt~ , O N V V H
H
H ~
* * * * * 'd'r-ir~
V V V
V
H
4-i . r-i O H N ch u1 h O '~ O H
r-1ri r1N ~
O
O p V
~,rj These results show that the tested compounds of the invention induce interferon biosynthesis at detectable levels in human whole blood and/or PBM cells over a wide range of dose concentrations.
1-SUBSTITUTED IH-IMIDAZO(4,5-C)QUINOLIN-4-AMINES; INTERMEDIATE AND PHARMACEUTI-CAL COMPOSITIONS
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to 1H-imidazo[4,5-c]-_ quinoline compounds. In other aspects, this invention relates to 1H-imidazo[4,5-c]quinolin-4-amines, intermediates for the preparation of such compounds, pharmaceutical compositions containing such compounds, and pharmacological methods of using such compounds.
Description of the Related Art The first reliable report of the 1H-imidazo-[4,5-c]quinoline ring system, Backman et al., J. Org.
Chem. 15, 1278-1284 (1950), describes the synthesis,of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]-quinoline for possible use as an antimalarial agent.
Subsequently; syntheses of various substituted 1H-imidazo[4,5-c]quinolines have been reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), has synthesized the compound 1-[2-(4-piperidyl)ethyl]-iH-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent.
Also, Baranov et al., Chem. Abp: 85, 94362.(1976), has reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chew. 18, 1537-1.540 (1981), has reported certain 2-oxoimidazo[4,5-c]-quinolines.
Certain antiviral 1H-imidazo[4,5-c]quinolin-4-amines are described in U.S. Pat. No. 4,689,338 (Gerster). These compounds are substituted on the 1-position by alkyl, hydroxyalkyl, acyloxyalkyl, benzyl, phenylethyl or substituted phenylethyl, and at the 2-position with hydrogen, alkyl, benzyl, or substituted benzyl, phenylethyl or phenyl. .
Furthermore, these compounds are known to induce interferon biosynthesis. Other antiviral 1H-imidazo[4,5-c)quinolin-4-amines, substituted on the 1-position by alkenyl substituents, are described in U.S. Pat. No. 4,929,624 (Gersterj.
U.S. Pat. No. 4,698,348 (Gersterj discloses iH-imidazo[4,5-c)quinolines that are active as bronchodilators, such as 4-substituted 1H-imidazo-[4,5-c]quinolines wherein the 4-substituent is, inter alia, hydrogen, chloro, alkylamino, or dialkylamino, and the 2-substituent is, inter alia, hydroxyalkyl, aminoalkyl, or alkanamidoalkyl. Said patent also discloses 3-amino and 3-nitro quinoline intermediates substituted at the 4-position by hydroxyalkylamino or cyclohexylmethylamino, and iH-imidazo[4,5-c)quinoline N-oxide intermediates substituted at the 2-position with, inter alia, hydroxyalkyl, aminoalkyl, or alkanamidoalkyl.
DETAILED DESCRIPTION OF THE INVENTION
This invention as broadly described hereinafter provides compounds of Forumula I:
NHS
N
N
N
i CHR1R'~
R
wherein R'1 is hydrogen or a carbon-carbon bond, with the proviso that when R', is hydrogen Ri is alkoxy of one tv about four carbon atoms, hydroxyalkoxy of one to about four carbon atoms, 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkaxy moiety contains one to about four carbon atoms and the alkyl moiety,contains one to about four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R'I is a carbon-carbon bond R', and R, together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to about four carbon atoms;
RZ is selected from the group consisting 'of hydrogen, alkyl of one to about four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms;
or a pharmaceutically acceptable acid addition salt thereof.
However, tr.e inventic>n as claimed excludes the compounds of formula I wherein R1 is 1-<~lkynyl.
The invention also provides intermediate compounds of the formula N /''1 ~ NHCH.,R
R
wherein R is as defined above, Y is -NOp or -NH2, and R4 is alkoxyalkyl wherein the alkoxy moiety ccmta:ins one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms.
The invention further provides intermediate compounds of the formula WO 93/05042 ~CT/US92/07226 . ''~~~J 4 _ Cl N O
\NHC~i2RS
R
wherein Y and R are as defined above and RS is 2-, 3-, or 4-pyridyl.
This invention provides intermediate compounds of the formula N ~1 ~ / R2 N
CH~Rg R
wherein R, Ra, and ~ are as defined above.
This invention provides intermediate , compounds of the formula 0 0+ N
N~ ~ . _ °N
t ~~~ CH~Ra R , wherein R, Rz, and R~ are as defined above.
Further this invention provides compounds of the formula WO 93/05042 -t ~ r ; ~ < f PCT/US92107226 ~:~Z~ ~~~~~~
N N
' R2 N
j~~ CH2R5 R
wherein R, R2, and R5 are as defined above.
This invention also provides intermediate compounds of the formula N~ N
~ ~°° R 2 ~N
R
wherein R and R2 are as defined above and R6 is alkanoyloxyalkoxy methyl or aroyloxyalkoxy methyl wherein the alkyl group contains one to about four carbon atoms, or tetrahydrofuranyl st,abstituted by one or more substituents independently selected from the . group consisting of alkanoylo~cy, aroyloxy, and alkanoyloxyalkyl and aroyloxyalkyl wherein the alkyl group contains one to about four carbon atoms.
R1 of Formula I is preferably alkoxyalkyl or 4-pyridyl.
Other substituents in compounds of Formula I
that contain an alkyl radical (e. g., R when R is alkoxy or alkyl) preferably contain two carbon atoms or, more preferably, one,carbon atom in each alkyl radical.
It is preferred that R of Formula I be hydrogen.
Preferred compounds of Formula I include:
1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-.4-amine;
1-(2-propynyl)-iH-imidazo[4,5-c]quinolin-4-amine;
1-[(tetrahydro-2H-pyran-2-yl)methyl]-1H-imidazo[4,5-c]-quinolin-4-amine; and 1-(2-pyridylmethyl)-iH-imidazo-[4,5-c]quinolin-4-amine.
Most preferred compounds of Formula I
include 1-(2-methoxypropyl)-2-methyl-1H~-imidazo[4,5-c]quinolin-4-amine, 1-(2-methoxyethyl)-l-methyl-1H-imidazo[4,5-c]quinolin-4-amine and ~.-(4-pyridylmethyl)-iH-imidazo[4,5-c]-quinolin-4-amine.
Compounds of Formula I can be prepared by alkylating the 1-position of a 1H-imidazo[4,5-c]-quinolin-4-amine with an alkylating agent of the formula (R' ~ ) (R~ ) HC-X wherein R' ~ and R~ are as defined above and X is chloro or bromo, in a polar solvent in the presence of sodium hydride. In instances Wherein R, comprises a hydroxyl group, the hydroxyl group can be protected for the alkylation step and subsequently deprotected. Suitable protecting groups include alkanoyloxy (e. g., acetoxy) ar aroyloxy (e. g., benzoyloxy or p-toloyloxy). Reactions for placement and removal of such groups are well known to those skilled in the art and disclosed, e.g., in U.S. Pat.
No. 4,689,338 (Gerster), Examples 115-123. 1H-Imidazo-[4,5-c]quinolin-4-amines can be prepared as set forth in Scheme I below:
WO 93/0S042 fCT/US92/07226 ,.1 Scheme I
N02 'N02 NOz NO c~ N~~ c~ NO
OH Cl ~NHRE
R II
R III R IV
C3) sO~N N ~) N N ~) N NH2 ~R2 ~ ~R2 'N ~N
RE RE NHRE
R VII R VI R V
Id N~ t~ N N C~ N N
~R~ ~ ~R2 ~ ~R2 _N -~N N
RE RE H
R R R
VIII IX X
In Scheme I, R and R2 are as defined above and RE is a substituent capable of being subjected to an elimination or like reaction to afford a 1.H-imidazo-[4,5-c~quinolin-4-amine. R~ can be any substituent that can be removed. Examples of general classes of RE
include groups that will yield a stable ration upon -w treatment with aqueous acid (e.ga tertiary substituents, meaning for the purposes caf the instant specification and claims any substituent wherein the carbon atom bonded to the 1-nitrogen is fully substituted with electron-donating groups, for example hydroxy, alkoxy, acyloxy, halogen, alkyl, phenyl, and the like) and substituents from which the 1H-imidazo[4,5-c]quinolin-4-amine can be eliminated (e. g.
2-hydroxyalkyl groups). Such RE substituents include 1,1-dimethylethyl (i.e., t-butyl), l,l-dimethyl-2-hydroxyethyl, 2-hydroxy-i-phenyl-1-methylethyl, 1,1-dimethyl-2-hydroxypropyl, and the like.
Many quinolines of Formula III are known compounds (see, for example, U.S. Pat. No. 3,700,674 and references cited therein). Those that are not known can be prepared by known methods, for example, from 4-hydroxy-3-nitroquinolines as illustrated in step (1) of Scheme I. Step (1) can be conducted by reacting the 4-hydroxy-3-nitroquinoline of Formula II with 1-2 moles of phosphorus oxychloride per mole of the 4-hydroxy-3-nitroquinoline of Formula II. The reaction can be conducted in N,N-dimethylformamide and can be accompanied by heating. In step (2) a 3-nitro-4-chloroquinoline of Formula III is reacted by heating with a compound of the formula RENH2, wherein RE
is as defined above, in a suitable solvent such as dichloromethane, water, or tetrahydrofuran, and optionally in the presence of a tertiary amine catalyst such as triethylamine to provide a quinoline of Formula IV.
Steps (1) and (2) can be combined such that the 3-nitro-4-chloroquinoline need not be, isolated prior to reaction with RENH2. Such a reaction is exemplified in Example 134 and Example 188 (Step A) of U.S. Pat. 4,689,338.
A compound of Formula IV is reduced in step (3) preferably using a catalyst such as platinum on charcoal, to provide a campound of Formula V. The reduction can be carried out conveniently on a Paar apparatus in an inert solvent such as toluene or a lower alkanol.
In step (4) an intermediate compound of Formula V is reacted with (i) a 1,1-dialkoxyalkyl alkanoate such as diethoxymethyl acetate, or (ii) a WO 93!05042 ~" ~' '"1 ~~ ~~ 6'CT/US92/07226 _ g _ carboxylic acid that will introduce the desired RZ
group, or (iii) a trialkyl ortho ester of the formula R2C(Oalkyl)3, wherein "alkyl" is an alkyl group containing 1 to about 4 carbon atoms, or (iv) a combination of such a carboxylic acid with such a trialkyl ortho ester to provide a compound of Formula VI. The reaction can be carried out by heating, e.g., at about 130°C, in the presence of an acid, preferably an alkanoic acid having one more carbon atom than R2.
Step (5) provides an intermediate of Formula VII. First, the hydroxy group, if ane is present in RE, is protected with, for example, an alkanoyloxy group such as acetoxy, or with benzoyloxy. Such protecting groups and reactions for their placement and removal are well known to those skilled in the art. See, for example, U.S. Pat. No. 4,689,338, Examples 115 to 123.
The resulting protected compound is then oxidized with a conventional oxidizing agent that is capable of forming N-oxides. Suitable oxidizing agents include 2o peroxyacids and hydrogen peroxide. Heating is generally employed to accelerate the rate of reaction.
In stag (6) an N-Qxide of Formula VII is first heated in the presence of a suitable chlorinating agent such as phosphorus oxychloride to provide an intermediate of Formula VIII. Phosphorus oxychloride can be used in combination with a solvent (e. g., dichloromethane) inert to conventional chlorinating agents, optionally in the presence of a catalytic amount of N,N-dimetl~ylformamide. The second part of step (6) involves removal of the protecting group, if one is present, by methods well known to those skilled in the art.
In step (7) the 4-chloro group is replaced by a 4-amino group to provide a compound of Formula IX.
The intermediate of Formula VIII can be heated, e.g., at 125° to 175°C under pressure for 6-24 hours in a sealed reactor in the presence of either ammonium hydroxide or a solution of ammonia in an alkanol, WO 93105042 PCfI US92/07226 _ 10 _ (e.g., 15% ammonia in methanol). In step (8), a compound of Formula IX is heated in the presence of .
aqueous acid to effect the deamination of the RE group, thus providing a 1H-imidazo[4,5-c]- quinolin-4-amine of Formula X. Preferred conditions for the reaction include brief (e. g., 30 minute) reflux in dilute (e. g.
4N) aqueous hydrochloric acid.
Another method of preparing compounds of Formula I involves the reactions shown in Scheme II
below. , Scheme II
NOZ
_ NO
R III
Cz) -C'+ N NC
NO ~R ( 2 ) N 2 N
~NHCH R
rH2R1 2 1.
R XII R XI
(3) N N
~T
a .fR
I
Steg 1 of Scheme II involves reacting a .' campound of Formula III in an inert solvent with an amine of the formula R~CHzNH2 to provide a compound of W~ 93/05042 Formula XI. The reaction of step 1 can be carried out in the presence of a tertiary amine catalyst (such as triethylamine).
Step 2 involves: (i) reduction of the vitro group of the compound of Formula XI as described above in connection with step (3) of Scheme I; (ii) reaction of the resulting 3-amino compound with a carboxylic acid or an equivalent thereof as described above in connection with step (4) of Scheme I in order to provide a cyclized imidazo[4,5-c]quinoline; and (iii) oxidizing the quinoline nitrogen as described above in connection with step (5) of Scheme I to provide the -w N-oxide of Formula XII.
~1 1H-imidazo~4,5-c]quinolin-4-amine is prepared in step (3) of the Scheme II. Step (3) involves (i) reacting a compound of Formula XII with an acylating, agent; (ii) reacting the product with an aminating agent; and (iii) isolating the compound of Formula I. Part (i) of step (3) involves reacting an N-oxide with an acylating agent. Suitable acylating agents include alkyl- or aryl- sulfonyl chlorides ~(e.g., benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. p-Toluenesulfonyl chloride is most preferred. Part (ii) of step (3) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e. g., ammonium carbonate, ammonium bicarbonate, and ammonium phosphate). Ammonium hydroxide is preferred. The reaction of step (3) is preferably carried out by dissolving the N-oxide of Formula XII in an inert solvent such as methylene chloride, adding the aminating agent to the solution, and then adding the acylating agent. Preferred conditions involve cooling to about 0°C to about 5°C
during the addition of the acylating agent. Heating or . , , ... . . , . . . ... . . .. .. . ..
.. ~,. ..41.. , . A... , .u. .....1~: _......... .. . e..Va'.e.. v r.'~. . -yd_.. v r W . .aa s.- . ~.. , . . . ~ ~ . .. . , . . a . .
WO 93/05042 ~''~'~~'~a PCT/US92/07226 =~~'~-'~.~
cooling can be used to control the rate of the reaction.
Compounds of Formula XIX, a subgenus of Formula I, can be prepared according to the general method disclosed in U.S. Pat. No. 4,988,815 (Andre et .. ' al.), as shown below in Scheme III, wherein R and R2 are as defined above and R~ is 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl alkoxyalkyl wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about four carbon atoms, 2-, 3-, or 4-pyridyl.
a III . ~
O O NOa HN' (1~.~ N I ~2~ O
OH pH ~
R I~ R %~ R ~
r ~ Q 3~ ~
N ~ ,~~
N
I
~2~
R ~ R ~ R ~ ..
O _ ~~--R2 ( _____.. . ..____.__ ..._.~. ...... ..".. .., .,a"..~, . . .. , " :~.~. .~...
;_. .....;. .~.:,~:. ... ... , .~...,~ ~- .... . .. ~;.. _., , .~-. . . ... .
, .
13 _ The unsubstituted compound of Formula XIII, 4-hydroxy-2(iH)-quinolinone, is a known, commercially available compound, and other compounds of Formula XIII
can be prepared therefrom by methods known to those skilled in the art. For example, Chg;m. Ber., 1927,~6~, 1108 (Kohler), discloses the preparation of 7-chloro-4-hydroxy-2(1H)-quinolinone.
In step (1) a compound of Formula XIII is nitrated at the 3-position using conventional nitration methods. It is known to those skilled in the art, however, that nitration is not necessarily selective.
For example, depending on the particular ~t substituent in a compound of Formula XIII and the particular conditions employed, nitration might occur on the benzo ring of a compound of Formula XIII. Those skilled in the art, however, are able to select appropriate conditions that will afford a compound of Formula XIV.
Suitable conditions involve mild heating (e.g., at about 40°C) with acetic acid as the solvent. The unsubstituted compound of Formula XIV, 4-hydroxy-3-nitro-2(1H)quinoline is known and the preparation thereof is disclosed in Chem. B_er_._, 1918, -5~.~ 1500 (Gabriel) .
In step (2) the nitrated compound of Formula XIV is chlorinated with a suitable chlorinating agent such as phosphorus pentachloride or phosphorus oxychloride to provide the dichloride product of Formula XV. The reaction can be carried out in an inert solvent or if appropriate in neat chlorinating agent. Mild heating serves to accelerate the rate of reaction. The unsubstituted compound of Formula XV, 2,4-chloro-3-nitroquinoline, is known and the preparation thereof is disclosed in Gabriel cited above.
The product of Formula XV can be isolated if desired, but steps (2) and (3) can be carried out without isolation of the compound of Formula XV. Such I~VO 93/05042 PC~'/US92/07226 - ~4 a process involves carrying out the reaction of step (2), careful hydrolysis of unreacted chlorinating agent at a relatively low temperature (e. g., below about 35°C), separating the organic layer, removing the product of Formula XV from the remaining aqueous layer by extraction with an organic solvent, and using the combined organic extracts as described below in connection with step (3).
In step (3), a compound of Formula XV is substituted at the 4-position by reaction with an excess of a compound of the formula RyCH2NH2, wherein R., is as defined above. It is sometimes necessary to use gentle heating (e. g., 50°C). This reaction proceeds selectively, affording only the~4-substituted product and no detectable amount of the 2-substituted compound.
The reaction is run in a solvent comprising a base such as triethylamine or pyridine. When step (3) is run independent of step (2), the reaction can be carried out in a neat basic solvent such as triethylamine.
Gentle heating (e. g., at about 70°C) is preferred.
In step (4), a compound of Formula XVI is reduced to afford a compound of Formula XVII. This reduction can be carried out by conventional methods such as by electrochemical reduction, by reaction with metals such as zinc, tin, or iron in acid, and by other conventional single step or multi-step methods known to thane skilled in the art. Suitable reduction conditions include conventional homogeneous or preferably heterogeneous catalytic hydrogenation conditions. A compound of Formula %VI is suspended or dissolved in a solvent such as ethanol, ethyl acetate, methanol, isopropyl alcohol, or mixtures thereof with acetic acid, in the presence of a suitable heterogeneous hydrogenation catalyst such as a platinum or rhodium on alumina, palladium on carbon, platinum on carbon, or the like under hydrogen pressure (e.g., 1-5 atm) in a steel bomb. Isopropyl alcohol is the preferred solvent.
WO 93/0j042 ~ '~ ~ ~ r~ ~~ F~ PCT/U592/07226 In step (5), a compound of Formula XVII is reacted with an orthoester or an orthoformate of the formula RZC (O-Alkyl) 3 or a carboxylic acid of the formula R2COZH or a mixture thereof, as described above in connection with step (4) of Scheme I.
In step (6), a compound of Formula XVIII is reacted with ammonia as described above in connection with step (7) of Scheme I to afford a compound of Formula XIX.
Compounds of Formula I can be isolated by the conventional means disclosed in U.S. Pat. No.
4,689,338 (Gerster), such as, for example, removal of the solvent and recrystallization from an appropriate solvent (e. g., N,N-dimethylformamide),or solvent mixture, or by dissolution in an appropriate solvent (such as methanol) and re-precipitation by addition of a second solvent in which the compound is insoluble.
A compound of Formula I can be used as an antiviral agent itself or it can be used in the form of a pharmaceutically acceptable acid-addition salt such as a hydrochloride, dihydrogen sulfate, trihydrogen phosphate, hydrogen nitrate, methar:.esulfonate or a salt of another pharmaceutically acceptable acid.
pharmaceutically acceptable acid-addition salt of a compound of Formula I can be prepared, generally by reaction of the compound with an equimolar amount of a relatively strong acid, preferably an inorganic acid such as hydrochloric, sulfuric, or phosphoric acid, or an organic acid such as methanesulfonic acid, in a polar solvent. Isolation of the salt is facilitated by the addition of a solvent, such as diethyl ether, in which the salt is insoluble.
A compound of the invention can be formulated for the various routes of administration in a pharmaceutically acceptable vehicle, such as water or polyethylene glycol, along with suitable adjuvants, excigients, and the like. Particular formulations will be easily selected by those skilled in the art.
dV0 93/05042 PCT/US92/07226 15 ~-Suitable formulations for topical application include creams, ointments and like formulations known to those skilled in the art. Formulations generally contain less than 10% by weight of a compound of Formula I, preferably about 0.1% to 5% by weight of a compound of Formula I.
The compounds of Formula I exhibit antiviral activity in mammals. They can therefore be used to control viral infections. For example, a compound of Formula I can be used as an agent to control infections in mammals caused by Type IT Herpes simplex virus.
Compounds of Formula I can also be used to treat a herpes infection by oral, topical, or intraperitoneal administration.
A number of compounds of Formula I were tested and found to induce biosynthesis of interferon in human_cells. The test methods and results are set forth below. These results suggest that at least certain compounds ~f the invention might be useful in treating ~ther diseases such as rheumatoid arthritis, warts, eczema, Hepatitis H, psoriasis, multiple rsclerosis, essential thrombocythemia, cancer such as basal cell carcinoma, and other neoplastic diseases.
In the following Examples, alI reactions were run with stirring under an atmosphere.of dry nitrogen unless otherwise indicated. The particular materials and amounts thereof recited in the Example, as well as other conditions and details, should not be construed to unduly limit the invention.
Example 1 1-Eth eth -1 -i 'dazo 5-c uin lin-4-amin A 0.48 g (0.012 mole) portion of 60% sodium hydride was added to a suspension of 2.0 g (0.011 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 20 mL of dimethylformamide. The resulting mixture was stirred for about 45 minutes until a solution was obtained. A
1.07 g (0.011 mole) portion of chloromethyl ethyl ether WO 93/05042 ~ ~ ,f ~~ PCl'/US92/07226 a,.
- i~ -was added to the solution. A precipitate formed immediately. The reaction mixture was stirred at room temperature for one hour. The precipitate was collected, slurried with water then dried to give 1.4 g of a solid which was identified as the 1-isomer by nuclear magnetic resonance spectroscopy. This solid was recrystallized from 150 mL of ethanol to provide 0.86 g of 1-ethoxymethyl-iH-imidazo[4,5-c]quinolin-4-amine, m.p. 255-261°C. Analysis: Calculated for C~3H~4N~0: %C, 64.4; %H, 5.8; %N, 23.1; Found: %C, 64.2;
%H 5.8, %N 22.8.
Example 2 ~-(2-Progy,~,~y~y-1H-imidazo[4:5-clcuinolin-4-amine Using the general method of Example 1, 2.1 g of iH-imidazo[4,5-c]quinolin-4-amine was reacted with 1.7 g of propargyl bromide to provide 0.4 g of 1-(2-propynyl)-1Ii-imidazo[4,5-c]quinolin-4-amine, m.p.
220-222°C. The structure was confirmed by nuclear magnetic resonance spectroscopy. Analysis: Calculated for Cl3H~oN4: %C, 70.3; %H, 4.5; %N, 25.2; Found: %C, 70.5; %H, 4.6; %N, 25.4.
n ..y'.
Example 3 1- f (Tetrahydro-2H-pyran-2 yly met~yrl ] -~H-imidazoj4 5-c]q ;no~.ip-4-amine, Using the general method of Example 1, 3.0 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with 2-bromomethyltetrahydropyran to provide about 2.5 g of a mixture of the 1 and 3 isomers. The mixture was slurried with about 30 mL of refluxing ethyl acetate then, cooled in, an, ice. bath. The resulting precipitate was collected and dried to provide 0.6 g of 1-[(tetrahydro-2H-pyran-2-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 206-210°C. The structure was confirmed by nuclear magnetic resonance spectroscopy . Analysis : Calculated f or C~6H1aN40: %C, _ _ _ __-._._r.___....,___.,...,_,..~..~.....,.,.,.a,. ~.- .._ . ,. T-ee.,,.~a..ea-rra.".c . .,..,z,~r~.. ~;.r,W ~<!s~rtT..~ . ,.
v,T.,dfl~.~,.6Y~,S~: . '.'T,T:V':::; .v.k'.,",H."'\a , ,.,.,'i:..1,~1.~... , ':.. , ... . . . .
r. f V4'O 93/05042 C~~ y ~- '~ PCT/ US92/07226 _ 18 _ 68.1; ~H, 6.4; ~N, 19.8; Found: ~C, 67.8; %H, 6.4; ~N, .
19.6. .
Example 4 1-Ll2-Acetoxyethoxv~meth~,l,]-iH-imidazo~ 4.5-clquinolin-4-amine Using the general method of Example 1, 5.0 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with (2-acetoxyethoxy)methyl bromide (prepared according to the method of Robins et al., Can. J. C,em. C0, 547 (1982)) to provide 5.3 g of a yellow solid. The solid was slurried with ethyl acetate to provide 2.3 g oa: a light yellow solid which was identified as the 1-isomer by nuclear magnetic resonance spectroscopy.
Example 5 1° C ~Ydro~ethaxv met 1,] -iH-in~ic~azo j 4,, 5-c Lg~ on lin-g-~~,i~n~
A 2.1 g portion of 1-[(2-acetoxyethoxy)-methyl]-iH-imidazo[4,5-c]quinolin-4-amine was combined with 25 mL of 15~ ammonia in methanol and stirred at room temperature fc~r about 16 hours. The resulting precipitate was collected, rinsed with ether and dried to provide 1.1 g of a solid. This solid was recrystallized from 50 mh of ethanol to provide 0.8 g of 1-[(2-hydroxyethoxy)]methyl-iH-imidazo[4,5- .
c]quinolin-4-amine as a yellow crystalline solid, m.p.
210-212°C. Analysis: Calculated for C'3H'$N4o2: ~C, 60.4; ~H, 5.5; %N, 21.7; FOUnd: ~C, 60.3; ~H, 5.5, %IJ, 21.5.
Example 6 1-(2-Deoxy-3.5-di-O-p-toluoy~-D-esythro pentofuranosyl) -1H-~midazo [4 45-c~quinolin-4-amine A 0.34 g (0.011 mole) portion of 60% sodium hydride was added to a suspension of 1.7 g (0.009 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 65 mL of methylene chloride. The reaction mixture was then .
diluted with 65 mL of acetonitrile and stirred at room temperature for 2 hours. 3.6 g (0.009 mole) of 2-deoxy-3,5-di-O-p-toluoyl-D-erythropentosyl chloride (prepared according to the method of Bhat, pp. 521-22 from Volume 1, Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson (1968)) was added to the reaction mixture and stirring at room temperature was continued for about 16 hours. The reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was evaporated to provide a residue which was purified by silica gel chromatography using ethyl acetate as the eluent to provide 1.4 g of the 3-isomer and 2.0 g of the 1-isomer. The structural assignments were confirmed by nuclear magnetic resonance spectroscopy.
Example 7 1- l2-Deoxv-B-D-ego _pentofuranosvl ) -~H-imidazo[4.5-clguinolin-4-amine A 2.2 g portion of 1-(2-deoxy-3,5-di-O-p-toluoyl-D-erythro-pentofuranosyl)-1H-imidazo[4,5-c]-quinolin-4-amine was dissolved in about 150 mL of 15%
ammonia in methanol and stirred at room temperature for about 48 hours. The volume of the reaction was reduced to about 50 mL and the precipitate collected to provide 0.56 g of a solid. The filtrate was evaporated and the residue was slurried with ether then ffiltered to provide 0.55 g of a solid. The two solids were combined then recrystallized from ethanol to provide 0.8 g of 1-(2-deoxy-~-D-erythro-pentofuranosyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 232-237°C.
Analysis: Calculated for CHSHt6N4O3: %C, 60.0; %H, 5.4;
%N, 18.7; Found: %C, 59.7; %H, 5.4; %N, 18.3.
Example 8 N-(2-Methoxvethyl)-3-vitro-4-guinolinamine A mixture containing 16 mL (0.22 mole) of thionyl chloride and 18 mL of dimethylformamide was ," , Z.~..., . w~ .:. ~. .
'5'.a .,c'i1~1,.~. ,..::.'".,):,:, :' 1, . ..;..4,., 'i 1 ~.
r.,.t .1 ~G. r rn.~ ' .,a ",. v?,. 4: ~a ' a .
. n:.~: .. . ~. r. ,' " ~.- . ~ .. a~ ~:-tt . . ,~. ~1~ ,, "_~.
~. n ...~,. . ya , ,....,R
. a..,a ' ~ . .v , rt w. , q ..
u'~S!. . .'t,. . 1~ . ~:
A.
...:fS .. c. h. ,.: ~.~ ~. , ~, . ct.,.; iY
..f.:.
.~...m~fa. .., ~ x. t "4. ,., " ..> ~_ 1: ., ~~~ . , q~,.. '< , a ,. . ~, ..,.
, n . i' a ~, , ru:~ ~..w , .:4':,t ...\. vt,... ~f c 'fit. b ~. » ' ~ t . .;Y ..~.. Z.~..
\ .
5.
.1 ! ~. ~'~.
.~. . . -;~. ., ..
.. . .. . , ., . . . ..a 5~ . . .~.. , .Z..,..2:~:...,. ,. . . ... 5.. .ri: s'G4f'nara.Zt..w. ,..»,...u.t....
.C~;,~:e,i. .,~,.~.:1.
al....'l...a~,.,a~~.tva....e.Jti'!.'2,.,.5.~~~~.e,~.."a:K, .
a.~.:.~~2~..~.w..~1."... a.~..~." _y._ ..tA.,-.. .$'r.... v .
V1!O 93/05042 PCT/US92/07226 t) 2 0 added to a suspension of 38 g (0.2 moles) of 4-hydroxy-3-nitroquinoline in 500 mL of dichloromethane. The resulting mixture was heated at reflux for 2 hours and then allowed to cool to room temperature. A 20 mL (0.23 mole) portion of methoxyethylamine was combined with 30 mL of triethylamine and the combination was slowly added with vigorous stirring to the reaction mixture. A vigorous heat of reaction was observed and the mixture was allowed to reflux until the heat of reaction dissipated. The reaction mixture was concentrated under vacuum to provide a residue which was then slurried with dilute hydrochloric acid. The slurry was filtered and the filtrate was made basic with ammonium hydroxide. The resulting precipitate was collected, rinsed with water and air dried to provide 37.4 g of a yellow solid. A sample of this material was recrystallized from ethanol-dichloromethane to provide N-(2-methoxyethyl)-3-nitro-4-quinolinamine as a yellow solid,' m.p. 113-115°C. Analysis: Calculated for Cl~i~3N3O3: %C, 58.3; %H, 5.3; %N, 17.0; Found: %C, 58.0;
%~i, 5.3; %N, 16.8.
Example 9 1-- (~-Methoxyethyl ) -2-methyl-7iH-imidazoj 4 . 5-c,~quinoline A mixture containing 12.5 g of N-(2-methoxyethyl)-3-nitro-4-quinolinamine, 0.6 g of 5%
platinum on carbon, 10 g of magnesium sulfate and 380 mh of ethyl acetate was hydrogenated in a Parr apparatus at an initial pressure of about 53 psi.
After the hydrogenation was complete, the reaction mixture was filtered. The filtrate was evaporated, under vacuum to provide the diamine intermediate as a clear amber oil. The oil was taken up in 150 mL of glacial acetic acid and the resulting solution was refluxed for one and a half hours before being evaporated under vacuum. The resulting residue was dissolved in water. The solution was made strongly 'I~VO 93/05042 P~1'/US92/07226 ~i.~ ~'~~'~
f F.~
basic with aqueous sodium hydroxide then extracted several times with ethyl acetate. The extracts were combined, dried over magnesium sulfate and evaporated.
The residue was slurried with ether/hexane then filtered to provide 9.5 g of crude product. A 0.5 g sample was recrystallized to provide pure 1-(2-methoxyethyl)-2-methyl-1H-imidazo[4,5-c]quinoline, m.p. 128-130°C. Analysis: Calculated for C,4H95N3o: %C, 69.7, %H, 6.3; %N, 17.4; Found: %C, 69.8j %H, 6.3, %N, 17.4.
Example 10 1- ( 2-~tethoxyet ~y~~ -2-methy -1H-imidazoj4 5-c,]quinol~n-4-amine I5 A 6.3 mL (0.03 male) portion of 32%
peracetic acid was added to a solution of 7.0 g (0.029 mole) of_1-(2-methoxyethyl)-2-methyl-iH-imidazo[4,5-c]quinoline in 100 mL of ethyl acetate.
The solution was heated at reflex for 30 minutes and then allowed to cool to room temperature. The resulting precipitate was collected, rinsed with a ..
small amount of ethyl acetate and dried to provide 7.7 g of the N-oxide as a solid. The N-oxide was dissolved in 125 mL of dichloromethane then mixed with 40 mL of concentrated ammonium hydroxide. The resulting heterogeneous mixture was stirred vigorously and cooled to 4°C. A 5.7 g (0.03 mole) portion of p-toluenesulfonyl chloride was dissolved in 25 mL, of dichloromethane and added dropwise to the mixture. The rate of addition was controlled such that the reaction mixture was maintained at a temperature of 4-9°C.
After the addition was completed the reaction mixture was allowed to stir at room temperature for one hour.
The dichloromethane was removed under vacuum. The w aqueous mixture was diluted further with water and the solid was collected, washed with water and dried to provide 6.1 g of crude product as a tan solid. The tan solid was recrystallized from methanol/dichloromethane W~ 93/05042 PCd'/~JS9210722b _ to provide 3.0 g of 1-(2-methaxyethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a colorless crystalline solid, m.p. 230-233°C. Analysis:
Calculated for C~4H16N4~~ %C, 65. fi; %H, 6.3; %N, 21.9;
Found: %C, 65.5; %H, 6.1; %N, 21.7.
Example 11 2-Chloro-3-vitro-N-°~2 gvrid~lmeth~,l)-4-auinolinamine A 8.2 g portion of 2,4-dichloro-3-nitroquinoline was dissolved in 85 mL of dimethylformamide. 2-(Aminomethyl)pyridine (2.5 mL) was added dropwise followed by the addition of 4.7 mh of triethylamine. The reaction mixture was stirred for minutes then an additional 1.0 mL.of 15 2-(aminomethyl)pyridine was added. The reaction mixture was stirred at room temperature for about an hour and then on a steam bath for about 45 minutes. -The reaction mixture was diluted with 1.50 mL of water.
The resulting precipitate was collected and dried to provide 7.3 g of a yellow brown solid. The solid was _slurried with about 75 mL of refluxing hexane then filtered while hot to give 4.5 g of a solid. A 200 mg sample was recrystallized from about 15 mh of ethanol to provide pure 2-chloro-3-vitro~N-(2-pyridylmethyl)-4-quinolinamine, m.p. 179-182°C. Analysis: Calculated fOr C~5C1H"N40~: %C, 57.2; %H, 3.5; %N, 17.8; FAUnd: %C, 57 . 4 ; %H, 3 . 6; %N, 17 0 7 s Example 12 2-Chloro-N4-(2-p~rid,~~lmethyl -3.4-~ainoline famine A mixture containing 5.8 g of 2-chloro-3-nitro~-N-(2-pyridylmethyl)-4-quinolinamine, 5.8 g of magnesium sulfate, 0:~ g of 5% platinum on carbon and 300 mL of ethyl acetate was hydrogenated on a Parr apparatus. After the hydrogenation was complete, the reaction mixture was filtered and the filtrate evaporated to provide 4.6 g of a solid. A sample was recrystallized from ethyl acetate/hexane to provide WO 93/USfl42 PCT/US92/07226 2~.~~'~'~~~
pure 2-chloro-N4-(2-pyridylmethyl)-3,4-quinolinediamine m.p. 98-102°C. Analysis: Calculated for C~SC1H13N4: %C, 63.3; %H, 4.6; %N, 19.7; Found %C, 63.5; %H, 4.7; %N, 19.8.
Example 13 4-Chloro-1-(~py~idylmethyl)-1H-imidazo_~'4 5-c~sruinoline A 1.6 mL portion diethoxymethyl acetate was added to a solution of 2.3 g of 4-Chloro-N~-(2-pyridyl-methyl)-3,4-quinolinediamine in 15 mL of warm xylene.
'the reaction mixture was heated on a steam bath for 90 minutes then diluted with hexane. The precipitate was collected and dried to provide 2.3 g.of a solid: A 300 mg sample was recrystallized from 10 mL of ethanol to provide pure 4-chloro-1-(2-pyridylmethylD-lI~-imidazo[4,5-caquinoline, m.p. 217-220°C. Analysis:
Calculated for C~gCIHi~Ndr %C, 65.2; %H, 3.8; %N, 3,9.0;
FOUnd: %C, 65.0; %H, 3.7; %N, 1$.8.
Example 14 1- 2- me H- 'd z 4 5- u' o 'ne A mixture of 2.4 g of 4-chloro-1-(2-pyridyl-methyl)-iH-imidazo[4,5-caquinoline and 50 mL of 15%
ammonia in methanol was placed in a bomb and heated at 150°C for 6 hours. After cooling, t:he reaction mixture was filtered. The solid was slurried with aqueous sodium bicar3aonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278-284°C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275-281°C. The two crops were combined for analysis. Analysis: Calculated for Ca6H~~Ns:
%C, 69.8; %H, 4.8; %N, 25.4; FOUnd %C, 69.7; %N, 4.8;
%N, 25.2.
WO 93/05042 PCT/US92/0?226 c,, r, .~ r~ ~ Ou.. i...:
Example 15 2-Chloro-3-vitro-N- ( 4-pvridvlmethvl ) -4-auinolinamine Using the general method of Example 11, 6.8 g of 2,4-dichloro-3-nitroquinoline was reacted with 4-(aminomethyl)pyridine to provide 7.8 g of crude 2-chloro-3-vitro-N-(4-pyridylmethyl)-4-quinolinamine.
This material was used without further purification.
Example 16 2-Chloro-N°-(4-pyridylmethvl -3.4-quinolinediamine Using the general method of Example 12, 5.0 g of 2-chloro-3-vitro-N-(4-pyridylmethyl)-4-quinolinamine was hydrogenated to provide 2.9 g of crude 2-chloro-N4-(4-pyridylmethyl)-3,4-quinoline-diamine. This material was used without further purification.
Example 1~
4-Chloro-1-(4-pyridylmethyl~-1H-imidazo 4.5-c~guinoline " A mixture containing 2.9 g of 2-chloro-N4-(4-pyridylmethyl)-3,4-guinolinediamine and 3 mL of diethoxymethyl acetate was heated on a steam bath for about 45 minutes. The reaction suspension was dissolved in cold dilute aqueous hydrochloric acid.
The solution was made basic with ammonium hydroxide.
The resulting oily solid was taken up in ethyl acetate and purified by silica gel chromatography using first ethyl acetate then 5% methanol in ethyl acetate as the eluent to provide 0.9 g of a solid. A 100 mg portion was recrystalli2ed from 5 mL of ethanol to provide 4-chloro-1-(4-pyridylmethyl)-1H-imidazo[4,5-c]-quinoline, m.p. >300°C. Analysis: Calculated for C16C1H~IN4: %C, 65.2, %H, 3.8, %N, 19.0; Found: %C, 64.8;
%H, 3.9; %N, 18.5.
WO 93/05042 PCT'/US92/07226 Example 18 1-(4-Pyridylmethvl)-1H-imidazo[4r5-clauinolin-4-amine Using the general method of Example 14, 0,8 g of 4-chloro-1-(4-pyridylmethyl)-1H-imidazo[4,5-c]quinoline was aminated to provide 0.25 g of 1-(4-pyridylmethyl)-iH-imidazo[4,5-c]quinolin-4-amine, m.p. >300°C. Analysis: Calculated for Cl6HisNs~ %C, 69.8;
%H, 4.8; %N, 25.4; Found: %C, 70.2; %H, 4.9; %N, 25.5.
Example 19 Part A
1- [ ( 3-Nitro-4 guinol inyl,~ amino, -2-propanol A mixture containing 16 mL (0.22 mole) of thionyl chloride in 18 mL of dimethylformamide was added with stirring to a suspension of 38 g (0.2 mole) of 9~-hydroxy-3-nitroquinoline. The resulting mixture was heated at reflux for 3 hours then cooled to -15°C
in a dry ace bath. A solution containing 18 mL (0.23 mole) of 1-amino-2-propanol and 30 mL (0.23 mole) triethylamine in 100 mL of methylene chloride was added dropwise with vigorous stirring to the chilled reaction mixture. After the addition was complete, the reaction mixture was heated at reflux for about 30 minutes. The reaction mixture was concentrated under vacuum to provide a yellow precipitate which was collected, rinsed with water and a small amount of ethanol and dried to provide 45 g of a yellow crystalline salid. A
1 g portion was recrystallized to provide 1-[(3-vitro- y 4-quinolinyl)amino]-2-propanol as a yellow crystalline solid, m.p. 209-210°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Part B
a,2-Dimethyl-iH-imidazol~4,5-c]quinoline-1--ethanol Using the general method of Example 9, 44.2 g of 1-[(3-vitro-4-quinnlinyl)amino]-2-propanol was hydrogenated to provide the intermediate diamine as a brown oil. Using the general method of Example 9, :», , .,. ~ . ,:;~ ,...
S" ~~'t . \.v.:'. v;.' .S . , . . .. r .... . . , ... . .,......, '..11'S~. ..mm.. ... . , ,.,. ~,:.~t , ..
"......,.. .,.. . ,..:i~.~,.. .. :,~..W ..... ....,.. ".v...:~.5~.,.....". a WO 93/05042 ,~~~D~~U.4~ PCT/U592/07226 17 g of the crude diamine was reacted with glacial acetic acid to provide 6.3 g of crude product. A
sample was recrystallized from ether to provide a,2-dimethyl-iH-imidazo[4,5-c]quinoline-1-ethanol as a blue tinged solid, m.p. 176-177°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Part C-1-l2-Methoxyprogyl)-2-methyl-iH-imidazoj4,5-c~guinoline Sodium hydride (1 g of 60%) was added to a suspension of 5 g (0.021 mole) of a,2-dimethyl-iH-imidazo[4,5-c]quinoline-1-ethanol in 100 mL of tetrahydrofuran. The resulting mixture was stirred for an hour. Methyl iodide (1.55 mL; 0.025 mole) was added and the reaction mixture was stirred for an hour. The reaction mixture was diluted with water then extracted three times with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of crude product as a brown oil. The oil was refluxed for one hour with 250 mL of hexane then filtered. The filtrate was cooled and the resulting precipitate was collected and dried to provide 2.4 g of a sticky light yellow powder. A sample was recrystallized from ether to provide 1-(2-methoxypropyl)-2-methyl-iH-imidazo[4,5-c]quinoline as a white crystalline solid, m.p. 55-57°C. ."
The structure was confirmed by nuclear magnetic resonance spectroscopy.
Example 20 1-(2-Methoxypro~vlf,]-2-methyl-1H-imidazo~4.5-clquinoline 5N ~~Cide Using the general method of Example 10, 2.4 g of 1-(2-methoxypropyl)-2-methyl-1H-imidazo[4,5-c]quinoline was oxidized using peracetic acid to provide 2.65 g of the crude N oxide as a yellow solid.
A 100 mg sample was recrystallized from ethyl acetate to provide d,-(2-methoxypropyl)-2-methyl-iH-imidazo[4,5-WU 93/05042 '" ~ ~ PCT/US92/07226 ~ ~. ; ~ '~ c.'. f c]quinoline 5N oxide as a solid, m.p. 146-149°C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Example 21 1- ~( 2-Methoxy~rogvl) -2-methyl ~~.Fi-~midazo j 4 . 5-cl ino~,in-4-am,~;ne Using the general method of Example 10, 2.55 g of 1-(2-methoxypropyl)-2-methyl-1H-imida~o[4,5-c]quinoline 5N oxide was aminated to provide 2.5 g of crude product as a light orange powder. The powder was recrystallized from ethyl acetate to provide 1.46 g of 1-(2-methoxypropyl)-2-methyl-iH-imida~o[4,5-c]quinolin-4-amine as a white crystalline solid,.m.p. 196-197'°C.
Analysis: Calculated for C~~H~8N40: %C, 66.6; %H, 6>?; %N, 20.7; Found: %C, 66.4; %H, 6.7; %N, 20.6.
Compounds of the invention were tested according to the test methods set forth below.
ANTIVIRA7L ACTIVITS~ AND
INTERFERON INDUCTION IN GUINEA hIGS
The test methods described below demonstrate the ability of compounds of the invention to xeduce the number and severity of lesions developed by guinea pigs infected with Type II Herpes simple5c virus and to induce the biosynthesis of interferon in guinea pigs.
Female Hartley guinea pigs weighing 200 to 250 g are anesthetized with methoxyflurane (available under the tradename METAFANET~'' from Fitman-Moore, Inc., Washington Crossing, NJ), after which the vaginal area is swabbed with a dry cotton swab. The guinea pigs are then infected intravaginally with a cotton swab saturated with Herpes simplex virus Type II strain 333 (1 X 10S plaque forming units/mL). Guinea pigs are assigned to groups of 7 animals; one group for each treatment and one to serve as a control (vehicle treated). The compounds of the invention are a n Cta:. r t/ y ~.'~~ - 2 8 -formulated in water containing 5% Tween 80 (a polyoxyethylene sorbitan monooleate available from Aldrich Chemical Company, Inc., Milwaukee, WI). The guinea pigs are treated orally once daily for four consecutive days starting 24 hours after infection.
Antivi~al Activitv Antiviral activity is evaluated by comparing lesion development in compound-treated versus vehicle-treated guinea pigs. External lesions are scored 4, 7, 8 and 9 days after infection using the following scale:
0 - no lesion, 1 - redness and swelling, 2 - a few small vesicles, 3 - several large vesicles, 4 - large ulcers with necrosis and 5 - paralysis. The maximum lesion score of each guinea pig is used to calculate the percentage lesion inhibition. The percentage lesion inhibition is calculated as follower Sum of maximum lesion scoops of treatment group x 100 100- Sum of maximum lesion scores of control group Inte,~feron Induction Twenty-four hours after the initial dose of test compound has been administered, blood is obtained from 3 guinea pigs from each treatment group by cardiac puncture of methoxyflurane anesthetized animals. Flood is pooled and allowed to clot at room temperature.
After low speed centrifugation, serum is collected and stored at -70°C until analysis.
Interferon levels in the guinea pig serum are determined in a standard microtiter essay using transformed guinea pig cells (ATCC CRL 1405). The interferon assay is done in 96 well microtiter plates.
Confluent monolayers of transformed guinea pig cells are treated with dilutions of guinea pig serum made with medium 199 (GIBCO, Grand Island, NY). The cell and serum dilutions are incubated at 37°C overnight.
-, ., . ___. . r . , . . . . . . . . . ...> ..~m .. . ~ .. , , . _...,.,... ,. . :,.~t..,.,:. ...". ."..,..,,... :.. ... ..
._u..,_... ~~ ..
WO 93/05042 ~ ~ 1 ~ ~ ~ t' PCT/US92/07226 The following day, the medium and serum are removed and about 10 plaque forming units of Mengavirus are added to each well. Controls consist of wells that receive no guinea pig serum (virus positive control) and wells that receive no virus (virus negative control). Cells and virus are incubated for 2 to 3 days at 37°C before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining with 0.05%
crystal violet followed by spectrophotometric absorbance measurements. The titer of interferon in serum is expressed as units/mL and is the reciprocal of the highest dilution that protects cells from virus.
Results are shown in the table below.
Antiviral Activity and Interferon Induction in Guinea Pigs 2o Compound of Dose % Lesion Reference example ~na/ka inhibition Units,fmL
1 2 55% not determined 2 2 5?% 600 14 2 20% not determined i8 2 0% not determined 18 5 88% a12,800 These results show that the tested compounds of the invention inhibit Herpes simplex virus type IT lesions in guinea pigs. Those compounds tested were also shown to induce interferon biosynthesis in guinea pigs.
WO 93/t~5042 PCT/US92/07226 cr; '~ ,;, INTERFERON-a INDUCTION IN HUMAN CELLS
The test methods described below demonstrate the ability of compounds of the invention to induce the biosynthesis of interferon-a in human cells.
An in vitro human blood cell system was used .
to assess interferon-a induction by compounds of the invention. Activity is based on the measurement of interferon secreted into culture medium. Interferon is measured by bioassay.
Blood Cell Preparation for Cu,~ture Whole blood is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBM's) are prepared by LeucoPREPT~'' Brand Cell Separation Tubes (available from Becton Dickinson) and cultured in RPMI 1640 medium (available from GIBCO, Grand Island, NY) containing 25 mM HEPES
4-(2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid and v-glutamine (1% penicillin-streptomycin solution added) with 10% autologous serum added. Alternatively, whole blood diluted 1:10 with RPMI 1640 medium supplemented with 25 mM HEPES and L-glutamine with 1%
penicillin-streptomycin solution added can be used.
200 ~ch portions Qf diluted whole blood or of PBM in medium are added to 96 well (flat bottom) MicroTest'~"III
tissue culture plates.
Compound Preparation The compounds are solubilized in water, ethanol, or dimethyl sulfoxide then diluted with dist~.lled water, 0.01N sodium hydroxide or 0.01N
hydrochloric acid. (The choice of solvent will depend on the chemical characteristics of the compound being tested.) ._ ~1 _ Incubation The solution of test compound is added (in a volume less than or equal to 50 ~L) to the wells containing 200 ~.L of PBM in medium or diluted whole blood. Solvent and/ar medium is added to control wells (i.e., wells with no test compound) and also as needed to adjust the final volume of each well to 250 uL. The plates are covered with plastic lids, vortexed gently and then incubated for 24 hours at 37°C with a 5%
carbon dioxide atmosphere.
Separation Following incubation, the plates are covered with PARAFILM~ and then centrifuged at 1000 rpm for 15 minutes at 4°C in a Damon IEC Model CRU-5000 centrifuge. Medium (about 175 ~L) is removed from 4 to 8 wells and pooled into 2 mL sterile freezing vials.
samples are maintained at -70°C until analysis.
Interferon Analysis Calculation Interferon i~; determined by bioassay using A549 human lung carcinoma cell chal.leng=>d with encephalo myocarditis. The details of the bioas:>ay method are described by G. L. Brerlnan and L. H. Kronenberg in "Automated Bioassay of Int:erferons in Micro-test Plates", Biotechniques, June/,Ju:Ly; 78, 195:3. Briefly stated the method is as follows: intEerferon di.l_utions and A549 cells are incubated at 37°c' ror 1.'<? t:o ~'4 I~~ours. The incubated cells are infected with an inoculum of encepha:Lomyocarditis virus. The infected cells are incubated for an additional period at 37 °C; before quant:i.f yind fc>r viral cytopathic effect. The viral cytopathic effect is quantified by staining followed b~~ spectrophot<arnetric absorbance - 31a -measurements. Results a.re expressed as a interferon reference units/mL based on the value obtained for NIH HU
IF-L standard. The interferon was identified as essentially W~O 93/05042 PCT/US92/07226 y ~' A
all interferon alpha by testing in checkerboard neutralization assays against rabbit anti-human interferon (beta) and goat anti-human interferon (alpha) using A549 cell monolayers challenged with encephalomyocarditis virus. Results are shown in the table below wherein the absence of an entry indicates that the compound was not tested at the particular dose concentration. Results designated as "~~~ a certain number indicate that interferon was not detectable in amounts above the lower sensitivity level of the assay.
wo 93iosoa2 w" ~ i ~t ~ ~° Sv ~~ Pcrius9zio~za~, J F,l d O
O p ~ W ~ ~ W
U ~
~ ~ ~
~ o 0 y c * * vv *
M r-d r-i t~ O e~ ,~ ct er O O C7O
"
r1 t e-1~p Ca tp Q~ M f~r1 li~ 1 r~i ' ' 1~
ey d ,d'h tn O fa * ~ * * * * * *
N r1 r x ~
0 0 ~co o o a ~-1 N * * ~ ~1 h c~1M
Q ~ ~ '~ V ~' m c~co , ..-i ~!
+~ ~ w ~ G ~ ~ ~
~ ~ p ,..~0 0 * *
N H v ' O V a-~ '~~
H G~IC
4.aO
O
pp * * * * v V M v O
%.a ~
* * * * * ~' ~ rt~ , O N V V H
H
H ~
* * * * * 'd'r-ir~
V V V
V
H
4-i . r-i O H N ch u1 h O '~ O H
r-1ri r1N ~
O
O p V
~,rj These results show that the tested compounds of the invention induce interferon biosynthesis at detectable levels in human whole blood and/or PBM cells over a wide range of dose concentrations.
Claims (13)
1. A compound of the formula:
wherein R'1 is hydrogen or a carbon-carbon bond, with the proviso that when R'1 is hydrogen R1 is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, thetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R'1 is carbon-carbon bond, R'1 and R1 together form a tetrahdyrofuranyl group optionally substituted with one or more substituents independently selected form the group consisting of hydroxy and hdyroxyalkyl of one to four carbon atoms;
R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms;
or a pharmaceutically acceptable acid addition salt thereof.
wherein R'1 is hydrogen or a carbon-carbon bond, with the proviso that when R'1 is hydrogen R1 is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, thetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R'1 is carbon-carbon bond, R'1 and R1 together form a tetrahdyrofuranyl group optionally substituted with one or more substituents independently selected form the group consisting of hydroxy and hdyroxyalkyl of one to four carbon atoms;
R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, wherein R1 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
3, A compound according to Claim 1, selected from the group consisting of 1-ethoxymethyl-1H-imidazo-[4,5-c]quinolin-4-amine, 1-(2-propynyl)-1H-imidazo-[4,5-c]quinolin-4-amine, 1-[(tetrahydro-2H-pyran-2-yl)-methyl]-1H-imidazo[4,5-c]-quinolin-4-amine, 1-(2-pyridylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine, 1-(2-methoxyethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine, 1-(4-pyridylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine, and 1-(2-methoxypropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
4. An antiviral pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable vehicle, the compound being present in an amount effective to inhibit and/or prevent the progress of a viral infection.
5. Use of a compound according to any one of claims 1 to 3, for inhibiting and/or preventing the infection in a mammal infected with a virus.
6. The use according to claim 5, wherein the virus is Type II Herpes simplex.
7. Use of a compound according to any one of claims 1 to 3 for inducing interferon biosynthesis in a mammal.
8. A compound of the formula:
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, Y is -NO2 or -NH2, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, Y is -NO2 or -NH2, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
9. A compound of the formula:
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing on to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and Y is -NO2 or -NH2, and R5 is 2-, 3-, or 4-pyridyl.
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing on to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and Y is -NO2 or -NH2, and R5 is 2-, 3-, or 4-pyridyl.
10. A compound of the formula:
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
11. A compound of the formula:
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atom, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atom, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R4 is alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms.
12. A compound of the formula wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R5 is 2-, 3-, or 4-pyridyl.
13. A compound of the formula:
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R6 is alkanoyloxyalkoxy methyl or aroyloxyalkoxy methyl wherein the alkyl group contains one to four carbon atoms, or tetrahydrofuranyl substituted by one or more substitutents independently selected from the group consisting of alkanoyloxy, aroyloxy, and alkanoyloxyalkyl and aroyloxyalkyl wherein the alkyl group contains one to four carbon atoms.
wherein R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, R2 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and R6 is alkanoyloxyalkoxy methyl or aroyloxyalkoxy methyl wherein the alkyl group contains one to four carbon atoms, or tetrahydrofuranyl substituted by one or more substitutents independently selected from the group consisting of alkanoyloxy, aroyloxy, and alkanoyloxyalkyl and aroyloxyalkyl wherein the alkyl group contains one to four carbon atoms.
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US07/754,610 US5268376A (en) | 1991-09-04 | 1991-09-04 | 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
PCT/US1992/007226 WO1993005042A1 (en) | 1991-09-04 | 1992-08-26 | 1-substituted 1h-imidazo(4,5-c)quinolin-4-amines; intermediate and pharmaceutical compositions |
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IL105325A (en) * | 1992-04-16 | 1996-11-14 | Minnesota Mining & Mfg | Immunogen/vaccine adjuvant composition |
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US5648516A (en) * | 1994-07-20 | 1997-07-15 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US5352784A (en) * | 1993-07-15 | 1994-10-04 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
US5644063A (en) * | 1994-09-08 | 1997-07-01 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-c]pyridin-4-amine intermediates |
ES2087038B1 (en) * | 1994-11-07 | 1997-03-16 | Uriach & Cia Sa J | NEW PIPERIDINES WITH ANTAGONIST ACTIVITY OF THE PAF. |
US5482936A (en) * | 1995-01-12 | 1996-01-09 | Minnesota Mining And Manufacturing Company | Imidazo[4,5-C]quinoline amines |
US5741908A (en) * | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
PT825186E (en) * | 1996-08-16 | 2002-08-30 | Pfizer | 2-AMINOBENZAZEPINE DERIVATIVES AND THEIR USE FOR IMMUNOSUPPRESSION TREATMENT |
US6039969A (en) | 1996-10-25 | 2000-03-21 | 3M Innovative Properties Company | Immune response modifier compounds for treatment of TH2 mediated and related diseases |
JP4101302B2 (en) * | 1997-01-09 | 2008-06-18 | テルモ株式会社 | Novel amide derivatives and synthetic intermediates |
JPH10298181A (en) * | 1997-04-25 | 1998-11-10 | Sumitomo Pharmaceut Co Ltd | Type 2 helper t cell selective immune response inhibitor |
US6777546B2 (en) * | 1997-10-07 | 2004-08-17 | Loma Linda University | Methods and substances for preventing and treating autoimmune disease |
AU2002300982B2 (en) * | 1997-12-11 | 2004-12-02 | Minnesota Mining And Manufacturing Company | Imidazonaphthyridines and their use in inducing cytokine biosynthesis |
UA67760C2 (en) * | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines |
US6110929A (en) * | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
DK1380587T3 (en) * | 1998-07-28 | 2006-07-17 | 3M Innovative Properties Co | Oxazolo, thiazolo and selenazolo [4,5-c] quinoline-4-amines and analogs thereof |
JP2000119271A (en) * | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | 1h-imidazopyridine derivative |
US6518280B2 (en) * | 1998-12-11 | 2003-02-11 | 3M Innovative Properties Company | Imidazonaphthyridines |
US6486168B1 (en) | 1999-01-08 | 2002-11-26 | 3M Innovative Properties Company | Formulations and methods for treatment of mucosal associated conditions with an immune response modifier |
CA2361936C (en) | 1999-01-08 | 2009-06-16 | 3M Innovative Properties Company | Formulations comprising imiquimod or other immune response modifiers for treating mucosal conditions |
US20020058674A1 (en) | 1999-01-08 | 2002-05-16 | Hedenstrom John C. | Systems and methods for treating a mucosal surface |
US6558951B1 (en) * | 1999-02-11 | 2003-05-06 | 3M Innovative Properties Company | Maturation of dendritic cells with immune response modifying compounds |
US6451810B1 (en) | 1999-06-10 | 2002-09-17 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
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US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6331539B1 (en) * | 1999-06-10 | 2001-12-18 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6573273B1 (en) | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
US6916925B1 (en) | 1999-11-05 | 2005-07-12 | 3M Innovative Properties Co. | Dye labeled imidazoquinoline compounds |
US6376669B1 (en) | 1999-11-05 | 2002-04-23 | 3M Innovative Properties Company | Dye labeled imidazoquinoline compounds |
JP3436512B2 (en) * | 1999-12-28 | 2003-08-11 | 株式会社デンソー | Accelerator device |
US6894060B2 (en) * | 2000-03-30 | 2005-05-17 | 3M Innovative Properties Company | Method for the treatment of dermal lesions caused by envenomation |
US20020110840A1 (en) * | 2000-12-08 | 2002-08-15 | 3M Innovative Properties Company | Screening method for identifying compounds that selectively induce interferon alpha |
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US6660747B2 (en) | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
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US6664264B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
UA74852C2 (en) * | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
US6677348B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
US6545016B1 (en) | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
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US6664265B2 (en) | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
WO2006091720A2 (en) * | 2000-12-08 | 2006-08-31 | 3M Innovative Properties Company | Compositions and methods for targeted delivery of immune response modifiers |
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UA74593C2 (en) * | 2000-12-08 | 2006-01-16 | 3M Innovative Properties Co | Substituted imidazopyridines |
US6645719B2 (en) * | 2001-06-05 | 2003-11-11 | Advanced Gene Technology Corporation | Herbal chip |
US7226928B2 (en) * | 2001-06-15 | 2007-06-05 | 3M Innovative Properties Company | Methods for the treatment of periodontal disease |
JP2005501550A (en) * | 2001-08-30 | 2005-01-20 | スリーエム イノベイティブ プロパティズ カンパニー | Maturation of plasmacytoid dendritic cells using immune response modifier molecules |
US20030139364A1 (en) * | 2001-10-12 | 2003-07-24 | University Of Iowa Research Foundation | Methods and products for enhancing immune responses using imidazoquinoline compounds |
DE60230340D1 (en) * | 2001-11-16 | 2009-01-22 | 3M Innovative Properties Co | N-Ä4- (4-amino-2-ethyl-1H-imidazoÄ4,5-quinolin-1-yl) -butyl-methanesulfonamide, pharmaceutical composition containing the same and their use |
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CA2365732A1 (en) * | 2001-12-20 | 2003-06-20 | Ibm Canada Limited-Ibm Canada Limitee | Testing measurements |
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ES2541132T3 (en) | 2002-02-22 | 2015-07-16 | Meda Ab | Method to reduce and treat UV-B-induced immunosuppression |
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ATE491471T1 (en) * | 2002-03-19 | 2011-01-15 | Powderject Res Ltd | ADJUVANTS FOR DNA VACCINES BASED ON IMIDAZOCINOLINE |
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GB0211649D0 (en) * | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
MXPA04012199A (en) * | 2002-06-07 | 2005-02-25 | 3M Innovative Properties Co | Ether substituted imidazopyridines. |
EP1545597B1 (en) | 2002-08-15 | 2010-11-17 | 3M Innovative Properties Company | Immunostimulatory compositions and methods of stimulating an immune response |
AU2003299082A1 (en) * | 2002-09-26 | 2004-04-19 | 3M Innovative Properties Company | 1h-imidazo dimers |
AU2003287324A1 (en) * | 2002-12-11 | 2004-06-30 | 3M Innovative Properties Company | Gene expression systems and recombinant cell lines |
WO2004053452A2 (en) * | 2002-12-11 | 2004-06-24 | 3M Innovative Properties Company | Assays relating to toll-like receptor activity |
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EP1599726A4 (en) * | 2003-02-27 | 2009-07-22 | 3M Innovative Properties Co | Selective modulation of tlr-mediated biological activity |
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US7163947B2 (en) * | 2003-03-07 | 2007-01-16 | 3M Innovative Properties Company | 1-Amino 1H-imidazoquinolines |
EP1605943A4 (en) * | 2003-03-07 | 2008-01-16 | 3M Innovative Properties Co | 1-amino 1h-imidazoquinolines |
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CA2518282C (en) * | 2003-03-13 | 2012-11-06 | 3M Innovative Properties Company | Methods of improving skin quality |
AU2004220465A1 (en) * | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Method of tattoo removal |
US20040192585A1 (en) * | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
US7893096B2 (en) | 2003-03-28 | 2011-02-22 | Novartis Vaccines And Diagnostics, Inc. | Use of small molecule compounds for immunopotentiation |
US20040202720A1 (en) * | 2003-04-10 | 2004-10-14 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
US20040265351A1 (en) | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
US20040214851A1 (en) * | 2003-04-28 | 2004-10-28 | 3M Innovative Properties Company | Compositions and methods for induction of opioid receptors |
US7731967B2 (en) | 2003-04-30 | 2010-06-08 | Novartis Vaccines And Diagnostics, Inc. | Compositions for inducing immune responses |
WO2004110991A2 (en) * | 2003-06-06 | 2004-12-23 | 3M Innovative Properties Company | PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES |
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TW200510412A (en) * | 2003-08-12 | 2005-03-16 | 3M Innovative Properties Co | Oxime substituted imidazo-containing compounds |
US7169926B1 (en) * | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
CA2535338C (en) * | 2003-08-14 | 2013-05-28 | 3M Innovative Properties Company | Substituted 1h-imidazo[4,5-c]pyridin-4-amines,1h-imidazo[4,5-c]quinolin -4-amines and 1h-imidazo[4,5-c]naphthyridin-4-amines as immune response modifiers |
JP2007504145A (en) * | 2003-08-25 | 2007-03-01 | スリーエム イノベイティブ プロパティズ カンパニー | Immunostimulatory combinations and treatments |
US8961477B2 (en) | 2003-08-25 | 2015-02-24 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
CA2536136C (en) | 2003-08-27 | 2012-10-30 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted imidazoquinolines |
JP2007504172A (en) * | 2003-09-02 | 2007-03-01 | スリーエム イノベイティブ プロパティズ カンパニー | Methods for treatment of mucosa related symptoms |
JP2007504269A (en) | 2003-09-05 | 2007-03-01 | スリーエム イノベイティブ プロパティズ カンパニー | Method for treating CD5 + B cell lymphoma |
EP1664342A4 (en) * | 2003-09-17 | 2007-12-26 | 3M Innovative Properties Co | Selective modulation of tlr gene expression |
WO2005033049A2 (en) * | 2003-10-01 | 2005-04-14 | Taro Pharmaceuticals U.S.A., Inc. | METHOD OF PREPARING 4-AMINO-1H-IMIDAZO(4,5-c)QUINOLINES AND ACID ADDITION SALTS THEREOF |
US20090075980A1 (en) * | 2003-10-03 | 2009-03-19 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and Analogs Thereof |
NZ546274A (en) | 2003-10-03 | 2009-12-24 | 3M Innovative Properties Co | Pyrazolopyridines and analags thereof |
JP5043435B2 (en) | 2003-10-03 | 2012-10-10 | スリーエム イノベイティブ プロパティズ カンパニー | Alkoxy substituted imidazoquinolines |
US7544697B2 (en) * | 2003-10-03 | 2009-06-09 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and analogs thereof |
AU2004285575A1 (en) * | 2003-10-31 | 2005-05-12 | 3M Innovative Properties Company | Neutrophil activation by immune response modifier compounds |
AU2004291122A1 (en) | 2003-11-14 | 2005-06-02 | 3M Innovative Properties Company | Hydroxylamine substituted imidazo ring compounds |
CN1906193A (en) * | 2003-11-14 | 2007-01-31 | 3M创新有限公司 | Oxime substituted imidazo ring compounds |
EP1686992A4 (en) | 2003-11-25 | 2009-11-04 | 3M Innovative Properties Co | Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
AR046781A1 (en) | 2003-11-25 | 2005-12-21 | 3M Innovative Properties Co | IMIDAZOQUINOLINE DERIVATIVES. PHARMACEUTICAL COMPOSITIONS. |
EP1689361A4 (en) * | 2003-12-02 | 2009-06-17 | 3M Innovative Properties Co | Therapeutic combinations and methods including irm compounds |
US20050226878A1 (en) * | 2003-12-02 | 2005-10-13 | 3M Innovative Properties Company | Therapeutic combinations and methods including IRM compounds |
WO2005076783A2 (en) * | 2003-12-04 | 2005-08-25 | 3M Innovative Properties Company | Sulfone substituted imidazo ring ethers |
WO2005066170A1 (en) | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
CA2552101A1 (en) * | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Piperazine, [1,4]diazepane, [1,4]diazocane, and [1,5]diazocane fused imidazo ring compounds |
WO2005066169A2 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinyl sulfonamides |
US20050239735A1 (en) * | 2003-12-30 | 2005-10-27 | 3M Innovative Properties Company | Enhancement of immune responses |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
AU2005222995B2 (en) * | 2004-03-15 | 2010-08-26 | 3M Innovative Properties Company | Immune response modifier formulations and methods |
WO2005094531A2 (en) | 2004-03-24 | 2005-10-13 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
EP1735010A4 (en) * | 2004-04-09 | 2008-08-27 | 3M Innovative Properties Co | Methods, compositions, and preparations for delivery of immune response modifiers |
JP2008505857A (en) * | 2004-04-28 | 2008-02-28 | スリーエム イノベイティブ プロパティズ カンパニー | Compositions and methods for mucosal vaccination |
WO2006078294A2 (en) | 2004-05-21 | 2006-07-27 | Novartis Vaccines And Diagnostics Inc. | Alphavirus vectors for respiratory pathogen vaccines |
US20050267145A1 (en) * | 2004-05-28 | 2005-12-01 | Merrill Bryon A | Treatment for lung cancer |
WO2005118555A1 (en) | 2004-06-04 | 2005-12-15 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US20080015184A1 (en) * | 2004-06-14 | 2008-01-17 | 3M Innovative Properties Company | Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines |
US8017779B2 (en) | 2004-06-15 | 2011-09-13 | 3M Innovative Properties Company | Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines |
US8541438B2 (en) | 2004-06-18 | 2013-09-24 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
WO2006009826A1 (en) | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines |
WO2006009832A1 (en) * | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Substituted imidazo ring systems and methods |
EP1765348B1 (en) * | 2004-06-18 | 2016-08-03 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
US7915281B2 (en) | 2004-06-18 | 2011-03-29 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method |
US7897609B2 (en) | 2004-06-18 | 2011-03-01 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
EP1768662A2 (en) | 2004-06-24 | 2007-04-04 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
CA2571421A1 (en) | 2004-06-24 | 2006-01-05 | Nicholas Valiante | Compounds for immunopotentiation |
WO2006019965A2 (en) * | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
US20060045886A1 (en) * | 2004-08-27 | 2006-03-02 | Kedl Ross M | HIV immunostimulatory compositions |
AU2005282726B2 (en) * | 2004-09-02 | 2011-06-02 | 3M Innovative Properties Company | 1-alkoxy 1H-imidazo ring systems and methods |
US20090270443A1 (en) * | 2004-09-02 | 2009-10-29 | Doris Stoermer | 1-amino imidazo-containing compounds and methods |
AU2005282523A1 (en) | 2004-09-02 | 2006-03-16 | 3M Innovative Properties Company | 2-amino 1H imidazo ring systems and methods |
US20080193468A1 (en) * | 2004-09-08 | 2008-08-14 | Children's Medical Center Corporation | Method for Stimulating the Immune Response of Newborns |
US20080213308A1 (en) * | 2004-09-14 | 2008-09-04 | Nicholas Valiante | Imidazoquinoline Compounds |
JP2008515928A (en) * | 2004-10-08 | 2008-05-15 | スリーエム イノベイティブ プロパティズ カンパニー | Adjuvants for DNA vaccines |
WO2006063072A2 (en) * | 2004-12-08 | 2006-06-15 | 3M Innovative Properties Company | Immunomodulatory compositions, combinations and methods |
US8080560B2 (en) * | 2004-12-17 | 2011-12-20 | 3M Innovative Properties Company | Immune response modifier formulations containing oleic acid and methods |
US8436176B2 (en) * | 2004-12-30 | 2013-05-07 | Medicis Pharmaceutical Corporation | Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine |
JP2008526765A (en) | 2004-12-30 | 2008-07-24 | スリーエム イノベイティブ プロパティズ カンパニー | Treatment of skin metastases |
WO2006074003A2 (en) | 2004-12-30 | 2006-07-13 | 3M Innovative Properties Company | CHIRAL FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS |
US8034938B2 (en) | 2004-12-30 | 2011-10-11 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
CA2592897A1 (en) * | 2004-12-30 | 2006-07-13 | Takeda Pharmaceutical Company Limited | 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate and 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate |
WO2006084251A2 (en) | 2005-02-04 | 2006-08-10 | Coley Pharmaceutical Group, Inc. | Aqueous gel formulations containing immune reponse modifiers |
AU2006338521A1 (en) | 2005-02-09 | 2007-10-11 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted thiazolo(4,5-c) ring compounds and methods |
AU2006212765B2 (en) | 2005-02-09 | 2012-02-02 | 3M Innovative Properties Company | Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines |
JP2008530113A (en) | 2005-02-11 | 2008-08-07 | コーリー ファーマシューティカル グループ,インコーポレイテッド | Oxime and hydroxyramine substituted imidazo [4,5-c] ring compounds and methods |
CA2597446A1 (en) * | 2005-02-11 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Substituted imidazoquinolines and imidazonaphthyridines |
SG164344A1 (en) | 2005-02-18 | 2010-09-29 | Novartis Vaccines & Diagnostics Srl | Immunogens from uropathogenic escherichia coli |
EP1858920B1 (en) | 2005-02-18 | 2016-02-03 | GlaxoSmithKline Biologicals SA | Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli |
US8178677B2 (en) | 2005-02-23 | 2012-05-15 | 3M Innovative Properties Company | Hydroxyalkyl substituted imidazoquinolines |
AU2006216686A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Method of preferentially inducing the biosynthesis of interferon |
AU2006216799A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazonaphthyridines |
JP2008531567A (en) | 2005-02-23 | 2008-08-14 | コーリー ファーマシューティカル グループ,インコーポレイテッド | Hydroxyalkyl-substituted imidazoquinoline compounds and methods |
MX2007011112A (en) * | 2005-03-14 | 2007-11-07 | Graceway Pharmaceuticals Llc | Method of treating actinic keratosis. |
US7943636B2 (en) | 2005-04-01 | 2011-05-17 | 3M Innovative Properties Company | 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases |
US7943610B2 (en) | 2005-04-01 | 2011-05-17 | 3M Innovative Properties Company | Pyrazolopyridine-1,4-diamines and analogs thereof |
JP2008539252A (en) * | 2005-04-25 | 2008-11-13 | スリーエム イノベイティブ プロパティズ カンパニー | Immune activation composition |
GB0510390D0 (en) * | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
EP2614709A1 (en) | 2005-07-18 | 2013-07-17 | Novartis AG | Small animal model for HCV replication |
EA200800782A1 (en) | 2005-09-09 | 2008-08-29 | Коли Фармасьютикал Груп, Инк. | AMIDA AND CARBAMATE DERIVATIVES N- {2- [4-AMINO-2- (ETOXIMETHYL) -1H-IMIDAZOLO [4,5-c] QUINOLIN-1-IL] -1,1-DIMETHYLETHYL} METHANE SULFONAMIDE AND METHODS |
ZA200803029B (en) | 2005-09-09 | 2009-02-25 | Coley Pharm Group Inc | Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods |
US8889154B2 (en) | 2005-09-15 | 2014-11-18 | Medicis Pharmaceutical Corporation | Packaging for 1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine-containing formulation |
WO2007047749A1 (en) | 2005-10-18 | 2007-04-26 | Novartis Vaccines And Diagnostics Inc. | Mucosal and systemic immunizations with alphavirus replicon particles |
EP1945252B1 (en) | 2005-11-04 | 2013-05-29 | Novartis Vaccines and Diagnostics S.r.l. | Vaccines comprising purified surface antigens prepared from influenza viruses grown in cell culture, adjuvanted with squalene |
JP2009514839A (en) | 2005-11-04 | 2009-04-09 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス エスアールエル | Adjuvant influenza vaccine containing cytokine inducer |
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WO2007081447A2 (en) | 2005-11-22 | 2007-07-19 | Novartis Vaccines And Diagnostics, Inc. | Norovirus and sapovirus antigens |
JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | PI-3 Kinase inhibitors and methods of their use |
JP6087041B2 (en) | 2006-01-27 | 2017-03-08 | ノバルティス アーゲー | Influenza virus vaccine containing hemagglutinin and matrix protein |
PE20070978A1 (en) * | 2006-02-14 | 2007-11-15 | Novartis Ag | HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks) |
WO2007100634A2 (en) | 2006-02-22 | 2007-09-07 | 3M Innovative Properties Company | Immune response modifier conjugates |
WO2007106854A2 (en) | 2006-03-15 | 2007-09-20 | Coley Pharmaceutical Group, Inc. | Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods |
WO2007109810A2 (en) * | 2006-03-23 | 2007-09-27 | Novartis Ag | Methods for the preparation of imidazole-containing compounds |
CA2646539A1 (en) * | 2006-03-23 | 2007-09-27 | Novartis Ag | Imidazoquinoxaline compounds as immunomodulators |
CA2646891A1 (en) * | 2006-03-23 | 2007-09-27 | Novartis Ag | Immunopotentiating compounds |
WO2007110776A1 (en) | 2006-03-24 | 2007-10-04 | Novartis Vaccines And Diagnostics Gmbh & Co Kg | Storage of influenza vaccines without refrigeration |
EP2382988A1 (en) | 2006-03-31 | 2011-11-02 | Novartis AG | Combined mucosal and parenteral immunization against HIV |
TW200808739A (en) * | 2006-04-06 | 2008-02-16 | Novartis Vaccines & Diagnostic | Quinazolines for PDK1 inhibition |
ATE522541T1 (en) | 2006-06-09 | 2011-09-15 | Novartis Ag | BACTERIAL ADHESIN CONFORMERS |
US7906506B2 (en) | 2006-07-12 | 2011-03-15 | 3M Innovative Properties Company | Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods |
GB0614460D0 (en) | 2006-07-20 | 2006-08-30 | Novartis Ag | Vaccines |
EP2586790A3 (en) | 2006-08-16 | 2013-08-14 | Novartis AG | Immunogens from uropathogenic Escherichia coli |
US8178539B2 (en) | 2006-09-06 | 2012-05-15 | 3M Innovative Properties Company | Substituted 3,4,6,7-tetrahydro-5H-1,2a,4a,8-tetraazacyclopenta[cd]phenalenes and methods |
ES2536401T3 (en) | 2006-09-11 | 2015-05-25 | Novartis Ag | Making vaccines against influenza viruses without using eggs |
CN109970735A (en) * | 2006-11-20 | 2019-07-05 | 诺华公司 | The salt and crystal form of compound |
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US20080149123A1 (en) | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
GB0700562D0 (en) | 2007-01-11 | 2007-02-21 | Novartis Vaccines & Diagnostic | Modified Saccharides |
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ES2561483T3 (en) | 2007-09-12 | 2016-02-26 | Glaxosmithkline Biologicals Sa | GAS57 mutant antigens and GAS57 antibodies |
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KR101773114B1 (en) | 2007-12-21 | 2017-08-30 | 노파르티스 아게 | Mutant forms of streptolysin o |
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JP5518041B2 (en) | 2008-03-18 | 2014-06-11 | ノバルティス アーゲー | Improvements in the preparation of influenza virus vaccine antigens |
US20100160368A1 (en) | 2008-08-18 | 2010-06-24 | Gregory Jefferson J | Methods of Treating Dermatological Disorders and Inducing Interferon Biosynthesis With Shorter Durations of Imiquimod Therapy |
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US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
WO2013061305A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Novel purine derivatives and their use in the treatment of disease |
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UY34536A (en) | 2011-12-22 | 2013-07-31 | Alios Biopharma Inc | NUCLEOSIDS REPLACED, NUCLEOTID AND ANALOG OF THE SAME |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
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USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
DK2844282T3 (en) | 2012-05-04 | 2019-07-15 | Pfizer | PROSTATA ASSOCIATED ANTIGENES AND VACCINE-BASED IMMUNTERAPIREGIMENES |
JP6381523B2 (en) | 2012-05-16 | 2018-08-29 | ノバルティス アーゲー | Administration regimen of PI-3 kinase inhibitor |
WO2014005958A1 (en) | 2012-07-06 | 2014-01-09 | Novartis Ag | Immunogenic compositions and uses thereof |
MX2015008773A (en) | 2013-01-07 | 2015-11-06 | Univ Pennsylvania | Compositions and methods for treating cutaneous t cell lymphoma. |
US9919029B2 (en) | 2013-07-26 | 2018-03-20 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of bacterial infections |
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EP2870974A1 (en) | 2013-11-08 | 2015-05-13 | Novartis AG | Salmonella conjugate vaccines |
JP2016539149A (en) | 2013-12-06 | 2016-12-15 | ノバルティス アーゲー | Alpha-isoform selective phosphatidylinositol 3-kinase inhibitor dosing regimen |
WO2015108595A1 (en) | 2014-01-15 | 2015-07-23 | Nikolai Khodarev | Anti-tumor therapy |
KR101644620B1 (en) | 2014-03-24 | 2016-08-01 | 충남대학교산학협력단 | Steel Rod or Wire Pile Connection for Civil and Building Structure |
ES2769647T3 (en) | 2014-03-26 | 2020-06-26 | Glaxosmithkline Biologicals Sa | Mutant Staphylococcal Antigens |
US10286065B2 (en) | 2014-09-19 | 2019-05-14 | Board Of Regents, The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
AU2016322813B2 (en) * | 2015-09-14 | 2021-04-01 | Pfizer Inc. | Novel imidazo (4,5-c) quinoline and imidazo (4,5-c)(1,5) naphthyridine derivatives as LRRK2 inhibitors |
WO2017059280A1 (en) | 2015-10-02 | 2017-04-06 | The University Of North Carolina At Chapel Hill | Novel pan-tam inhibitors and mer/axl dual inhibitors |
AU2016347881A1 (en) | 2015-11-02 | 2018-05-10 | Novartis Ag | Dosage regimen for a phosphatidylinositol 3-kinase inhibitor |
KR20180134395A (en) | 2016-04-19 | 2018-12-18 | 인네이트 튜머 이뮤니티, 인코포레이티드 | NLRP3 modulator |
US10533007B2 (en) | 2016-04-19 | 2020-01-14 | Innate Tumor Immunity, Inc. | NLRP3 modulators |
KR102497742B1 (en) | 2016-08-30 | 2023-02-10 | 다나-파버 캔서 인스티튜트 인크. | Drug Delivery Compositions and Uses Thereof |
WO2018060833A1 (en) | 2016-09-27 | 2018-04-05 | Novartis Ag | Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib |
CA3043480A1 (en) | 2016-11-09 | 2018-05-17 | The Board Of Regents Of The University Of Texas System | Methods and compositions for adaptive immune modulation |
TWI674261B (en) | 2017-02-17 | 2019-10-11 | 美商英能腫瘤免疫股份有限公司 | Nlrp3 modulators |
EP3728255B1 (en) | 2017-12-20 | 2022-01-26 | 3M Innovative Properties Company | Amide substituted imidazo[4,5-c]quinoline compounds with a branched chain linking group for use as an immune response modifier |
CA3034912A1 (en) | 2018-02-28 | 2019-08-28 | Pfizer Inc. | Il-15 variants and uses thereof |
TWI793325B (en) | 2018-05-23 | 2023-02-21 | 美商輝瑞大藥廠 | Antibodies specific for cd3 and uses thereof |
EP3796983A2 (en) | 2018-05-23 | 2021-03-31 | Pfizer Inc. | Antibodies specific for gucy2c and uses thereof |
US20220370606A1 (en) | 2018-12-21 | 2022-11-24 | Pfizer Inc. | Combination Treatments Of Cancer Comprising A TLR Agonist |
WO2021116420A1 (en) | 2019-12-13 | 2021-06-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of tlr7 and/or tlr8 agonists for the treatment of leptospirosis |
IL293926A (en) | 2019-12-17 | 2022-08-01 | Pfizer | Antibodies specific for cd47, pd-l1, and uses thereof |
TW202216779A (en) | 2020-07-17 | 2022-05-01 | 美商輝瑞股份有限公司 | Therapeutic antibodies and their uses |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA848968B (en) * | 1983-11-18 | 1986-06-25 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines |
IL73534A (en) * | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
DK0385630T3 (en) * | 1989-02-27 | 1997-05-12 | Riker Laboratories Inc | 1H-imidazo (4,5-c) quinoline-4-amines as antivirals |
US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
US4988815A (en) * | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
US5389640A (en) * | 1991-03-01 | 1995-02-14 | Minnesota Mining And Manufacturing Company | 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines |
US5266575A (en) * | 1991-11-06 | 1993-11-30 | Minnesota Mining And Manufacturing Company | 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines |
-
1991
- 1991-09-04 US US07/754,610 patent/US5268376A/en not_active Expired - Lifetime
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1992
- 1992-08-21 US US07/933,408 patent/US5346905A/en not_active Expired - Lifetime
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- 1992-08-26 WO PCT/US1992/007226 patent/WO1993005042A1/en active IP Right Grant
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- 1992-08-26 KR KR1019940700693A patent/KR100233313B1/en not_active IP Right Cessation
- 1992-08-26 ES ES92919122T patent/ES2150918T3/en not_active Expired - Lifetime
- 1992-08-26 CZ CZ94487A patent/CZ281726B6/en not_active IP Right Cessation
- 1992-08-26 DK DK92919122T patent/DK0603251T3/en active
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1994
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US5268376A (en) | 1993-12-07 |
WO1993005042A1 (en) | 1993-03-18 |
HU223947B1 (en) | 2005-03-29 |
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HU217715B (en) | 2000-04-28 |
IL102951A (en) | 1997-09-30 |
NZ244075A (en) | 1995-05-26 |
PH30132A (en) | 1997-01-21 |
US5525612A (en) | 1996-06-11 |
EP0603251B1 (en) | 2000-10-18 |
HU9701448D0 (en) | 1997-10-28 |
HUT67398A (en) | 1995-04-28 |
DK0603251T3 (en) | 2001-01-02 |
CZ281726B6 (en) | 1996-12-11 |
HU9403112D0 (en) | 1995-02-28 |
HU211624A9 (en) | 1995-12-28 |
JPH06510299A (en) | 1994-11-17 |
JP3315983B2 (en) | 2002-08-19 |
US5346905A (en) | 1994-09-13 |
AU2514792A (en) | 1993-04-05 |
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