NO316687B1 - Imidazonaftyridiner, farmasoytiske blandinger inneholdende imidazon og deres anvendelse til a indusere cytokin biosyntese - Google Patents

Info

Publication number

NO316687B1

NO316687B1 NO20002663A NO20002663A NO316687B1 NO 316687 B1 NO316687 B1 NO 316687B1 NO 20002663 A NO20002663 A NO 20002663A NO 20002663 A NO20002663 A NO 20002663A NO 316687 B1 NO316687 B1 NO 316687B1

Authority

NO

Norway

Prior art keywords

alkyl

optionally substituted

phenyl

halogen

group

Prior art date

1997-12-11

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• 102000004127 Cytokines Human genes 0.000 title claims abstract description 27
• 108090000695 Cytokines Proteins 0.000 title claims abstract description 27
• 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
• VFTLXHXYGQSOEN-UHFFFAOYSA-N 1h-imidazo[4,5-b][1,8]naphthyridine Chemical class C1=CN=C2NC3=NC=NC3=CC2=C1 VFTLXHXYGQSOEN-UHFFFAOYSA-N 0.000 title abstract 2
• 239000008194 pharmaceutical composition Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 279
• 229910052739 hydrogen Inorganic materials 0.000 claims description 234
• 229910052799 carbon Inorganic materials 0.000 claims description 179
• 125000000217 alkyl group Chemical group 0.000 claims description 111
• 239000000203 mixture Substances 0.000 claims description 73
• 229910052736 halogen Inorganic materials 0.000 claims description 66
• 150000002367 halogens Chemical class 0.000 claims description 66
• -1 -OH Chemical group 0.000 claims description 55
• 239000001257 hydrogen Substances 0.000 claims description 55
• 125000001072 heteroaryl group Chemical group 0.000 claims description 48
• 125000001424 substituent group Chemical group 0.000 claims description 46
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• 125000000623 heterocyclic group Chemical group 0.000 claims description 39
• 125000004076 pyridyl group Chemical group 0.000 claims description 28
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
• 241001465754 Metazoa Species 0.000 claims description 19
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 125000001544 thienyl group Chemical group 0.000 claims description 19
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 18
• 150000003839 salts Chemical class 0.000 claims description 18
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 14
• 125000003118 aryl group Chemical group 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 10
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 10
• 125000002541 furyl group Chemical group 0.000 claims description 10
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 10
• 125000002757 morpholinyl group Chemical group 0.000 claims description 10
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 9
• 125000005053 dihydropyrimidinyl group Chemical group N1(CN=CC=C1)* 0.000 claims description 9
• 125000002883 imidazolyl group Chemical group 0.000 claims description 9
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
• 208000036142 Viral infection Diseases 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 230000009385 viral infection Effects 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 150000002431 hydrogen Chemical group 0.000 claims description 6
• 230000001939 inductive effect Effects 0.000 claims description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 5
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000004414 alkyl thio group Chemical group 0.000 claims description 5
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 2
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 2
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 48
• 108010050904 Interferons Proteins 0.000 abstract description 21
• 102000014150 Interferons Human genes 0.000 abstract description 21
• 229940079322 interferon Drugs 0.000 abstract description 20
• 239000000543 intermediate Substances 0.000 abstract description 17
• 238000002360 preparation method Methods 0.000 abstract description 15
• 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 10
• 102000003390 tumor necrosis factor Human genes 0.000 abstract description 8
• 230000000840 anti-viral effect Effects 0.000 abstract description 2
• ZZXQWFQBPSUCAF-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-imidazo[4,5-b][1,8]naphthyridine Chemical class N1C2=NC=CC=C2C=C2C1NCN2 ZZXQWFQBPSUCAF-UHFFFAOYSA-N 0.000 abstract 1
• 230000000259 anti-tumor effect Effects 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 465
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
• 229910052757 nitrogen Inorganic materials 0.000 description 182
• 239000011541 reaction mixture Substances 0.000 description 128
• 239000007787 solid Substances 0.000 description 102
• 238000006243 chemical reaction Methods 0.000 description 101
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
• 238000004458 analytical method Methods 0.000 description 91
• 239000000243 solution Substances 0.000 description 91
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 89
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
• 229910001868 water Inorganic materials 0.000 description 73
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 60
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 58
• 239000000047 product Substances 0.000 description 47
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 44
• 235000019341 magnesium sulphate Nutrition 0.000 description 44
• 239000000741 silica gel Substances 0.000 description 44
• 229910002027 silica gel Inorganic materials 0.000 description 44
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 41
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
• 239000010410 layer Substances 0.000 description 37
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 30
• 238000002844 melting Methods 0.000 description 27
• 230000008018 melting Effects 0.000 description 27
• 239000000843 powder Substances 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 26
• 239000002244 precipitate Substances 0.000 description 26
• 238000004809 thin layer chromatography Methods 0.000 description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
• 239000000725 suspension Substances 0.000 description 24
• 239000003054 catalyst Substances 0.000 description 23
• 238000010828 elution Methods 0.000 description 23
• 239000000706 filtrate Substances 0.000 description 23
• 239000003921 oil Substances 0.000 description 23
• 235000019198 oils Nutrition 0.000 description 23
• 238000003818 flash chromatography Methods 0.000 description 22
• RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 21
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
• 230000003197 catalytic effect Effects 0.000 description 18
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
• 238000005481 NMR spectroscopy Methods 0.000 description 17
• 238000010438 heat treatment Methods 0.000 description 17
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 15
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 239000000908 ammonium hydroxide Substances 0.000 description 15
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
• 239000002253 acid Substances 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• UDPCXSIHDFYJJJ-UHFFFAOYSA-N 1-(4-aminobutyl)-2-butylimidazo[4,5-c][1,5]naphthyridin-4-amine Chemical compound C1=CC=NC2=C(N(C(CCCC)=N3)CCCCN)C3=C(N)N=C21 UDPCXSIHDFYJJJ-UHFFFAOYSA-N 0.000 description 13
• 239000012044 organic layer Substances 0.000 description 13
• 239000003795 chemical substances by application Substances 0.000 description 12
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 12
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 12
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 11
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• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 11
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
• URVRUEIJYPBVSU-UHFFFAOYSA-N 1-(2-aminoethyl)-2-butylimidazo[4,5-c][1,5]naphthyridin-4-amine Chemical compound C1=CC=NC2=C(N(C(CCCC)=N3)CCN)C3=C(N)N=C21 URVRUEIJYPBVSU-UHFFFAOYSA-N 0.000 description 10
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• 150000001412 amines Chemical class 0.000 description 10
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• 238000012360 testing method Methods 0.000 description 10
• 230000003612 virological effect Effects 0.000 description 10
• FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
• 230000006698 induction Effects 0.000 description 9
• MIDQVYLLSDOPIL-UHFFFAOYSA-N 1,5-naphthyridine-3,4-diamine Chemical compound C1=CC=NC2=C(N)C(N)=CN=C21 MIDQVYLLSDOPIL-UHFFFAOYSA-N 0.000 description 8
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• 201000010099 disease Diseases 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 8
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• 229910003446 platinum oxide Inorganic materials 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 7
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• 239000012299 nitrogen atmosphere Substances 0.000 description 6
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• 238000010992 reflux Methods 0.000 description 6
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• FDOIXMGDTOEUQL-UHFFFAOYSA-N 4-chloro-3-nitro-1,5-naphthyridine Chemical compound C1=CC=NC2=C(Cl)C([N+](=O)[O-])=CN=C21 FDOIXMGDTOEUQL-UHFFFAOYSA-N 0.000 description 4
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
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