TW200528094A - Macrocyclic peptides active against the hepatitis c virus - Google Patents

Info

Publication number

TW200528094A

TW200528094A TW094101708A TW94101708A TW200528094A TW 200528094 A TW200528094 A TW 200528094A TW 094101708 A TW094101708 A TW 094101708A TW 94101708 A TW94101708 A TW 94101708A TW 200528094 A TW200528094 A TW 200528094A

Authority

TW

Taiwan

Prior art keywords

alkyl

group

cycloalkyl

compound

substituted

Prior art date

2004-01-21

Links

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• 241000711549 Hepacivirus C Species 0.000 title claims description 43
• 108090000765 processed proteins & peptides Proteins 0.000 title description 4
• 102000004196 processed proteins & peptides Human genes 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 192
• 239000003112 inhibitor Substances 0.000 claims abstract description 57
• 150000003839 salts Chemical class 0.000 claims abstract description 42
• 150000002148 esters Chemical class 0.000 claims abstract description 25
• 125000000217 alkyl group Chemical group 0.000 claims description 412
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 141
• -1 Het Chemical group 0.000 claims description 127
• 125000001424 substituent group Chemical group 0.000 claims description 89
• 239000000460 chlorine Substances 0.000 claims description 87
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 86
• 239000000203 mixture Substances 0.000 claims description 84
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 61
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
• 229910052736 halogen Inorganic materials 0.000 claims description 52
• 150000002367 halogens Chemical class 0.000 claims description 52
• 239000003795 chemical substances by application Substances 0.000 claims description 47
• 125000003118 aryl group Chemical group 0.000 claims description 44
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
• 125000000304 alkynyl group Chemical group 0.000 claims description 36
• 125000003342 alkenyl group Chemical group 0.000 claims description 35
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 33
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 33
• 229920006395 saturated elastomer Polymers 0.000 claims description 33
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
• 229940079322 interferon Drugs 0.000 claims description 31
• 238000000034 method Methods 0.000 claims description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
• 108010050904 Interferons Proteins 0.000 claims description 26
• 102000014150 Interferons Human genes 0.000 claims description 26
• 241000124008 Mammalia Species 0.000 claims description 26
• 108091005804 Peptidases Proteins 0.000 claims description 25
• 239000004365 Protease Substances 0.000 claims description 25
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 102000035195 Peptidases Human genes 0.000 claims description 23
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 23
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
• 125000005842 heteroatom Chemical group 0.000 claims description 21
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
• 230000010076 replication Effects 0.000 claims description 20
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 19
• 239000003443 antiviral agent Substances 0.000 claims description 19
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
• 229910052794 bromium Inorganic materials 0.000 claims description 19
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 19
• 125000004432 carbon atom Chemical group C* 0.000 claims description 18
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 18
• 241000700605 Viruses Species 0.000 claims description 17
• 239000007789 gas Substances 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 17
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
• RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims description 16
• 229910052717 sulfur Inorganic materials 0.000 claims description 16
• 239000011737 fluorine Substances 0.000 claims description 15
• 229910052731 fluorine Inorganic materials 0.000 claims description 15
• 125000004104 aryloxy group Chemical group 0.000 claims description 13
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
• 125000000468 ketone group Chemical group 0.000 claims description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
• 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 12
• 125000001188 haloalkyl group Chemical group 0.000 claims description 12
• 150000001335 aliphatic alkanes Chemical group 0.000 claims description 11
• 239000000126 substance Substances 0.000 claims description 11
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 230000005764 inhibitory process Effects 0.000 claims description 10
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 208000015181 infectious disease Diseases 0.000 claims description 9
• 230000002401 inhibitory effect Effects 0.000 claims description 9
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
• 229920002554 vinyl polymer Polymers 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 8
• 208000010710 hepatitis C virus infection Diseases 0.000 claims description 8
• 125000005647 linker group Chemical group 0.000 claims description 8
• 125000002950 monocyclic group Chemical group 0.000 claims description 8
• 208000005176 Hepatitis C Diseases 0.000 claims description 7
• 239000002955 immunomodulating agent Substances 0.000 claims description 7
• 229940121354 immunomodulator Drugs 0.000 claims description 7
• 125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 7
• 239000000052 vinegar Substances 0.000 claims description 7
• 235000021419 vinegar Nutrition 0.000 claims description 7
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 6
• 102000004190 Enzymes Human genes 0.000 claims description 6
• 108090000790 Enzymes Proteins 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 208000006454 hepatitis Diseases 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
• 238000006467 substitution reaction Methods 0.000 claims description 6
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
• 108060004795 Methyltransferase Proteins 0.000 claims description 5
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000002541 furyl group Chemical group 0.000 claims description 4
• 230000002584 immunomodulator Effects 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 150000003852 triazoles Chemical class 0.000 claims description 4
• 108010047761 Interferon-alpha Proteins 0.000 claims description 3
• 102000006992 Interferon-alpha Human genes 0.000 claims description 3
• 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 3
• 239000007983 Tris buffer Substances 0.000 claims description 3
• 239000002671 adjuvant Substances 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 3
• 229910052739 hydrogen Inorganic materials 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 3
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
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• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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• RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 3
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
• LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims 2
• 125000002757 morpholinyl group Chemical group 0.000 claims 2
• BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 2
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• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims 1
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• YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
• ZTVIKZXZYLEVOL-DGKWVBSXSA-N 2-hydroxy-2-phenylacetic acid [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] ester Chemical group C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-DGKWVBSXSA-N 0.000 claims 1
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