ES2297424T3 - Compuestos inhibidores de la hepatitis c. - Google Patents

Info

Publication number

ES2297424T3

ES2297424T3 ES04733750T ES04733750T ES2297424T3 ES 2297424 T3 ES2297424 T3 ES 2297424T3 ES 04733750 T ES04733750 T ES 04733750T ES 04733750 T ES04733750 T ES 04733750T ES 2297424 T3 ES2297424 T3 ES 2297424T3

Authority

ES

Spain

Prior art keywords

alkyl

cycloalkyl

baselineskip

compound according

mmol

Prior art date

2003-05-21

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 222
• 230000002401 inhibitory effect Effects 0.000 title description 9
• 208000006454 hepatitis Diseases 0.000 title description 4
• 231100000283 hepatitis Toxicity 0.000 title description 4
• 239000003112 inhibitor Substances 0.000 claims abstract description 55
• 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims abstract description 25
• 208000005176 Hepatitis C Diseases 0.000 claims abstract description 16
• 230000009385 viral infection Effects 0.000 claims abstract description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 222
• -1 3,3,3-trifluoropropyl Chemical group 0.000 claims description 124
• 239000000203 mixture Substances 0.000 claims description 112
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 95
• 239000003795 chemical substances by application Substances 0.000 claims description 53
• 241000711549 Hepacivirus C Species 0.000 claims description 52
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
• 125000001424 substituent group Chemical group 0.000 claims description 39
• 229910052736 halogen Inorganic materials 0.000 claims description 37
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 36
• 150000002148 esters Chemical class 0.000 claims description 36
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
• 150000003839 salts Chemical class 0.000 claims description 36
• 108010050904 Interferons Proteins 0.000 claims description 34
• 102000014150 Interferons Human genes 0.000 claims description 34
• 150000002367 halogens Chemical group 0.000 claims description 32
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 30
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
• SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 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 25
• 241000124008 Mammalia Species 0.000 claims description 24
• 125000004429 atom Chemical group 0.000 claims description 24
• 239000003443 antiviral agent Substances 0.000 claims description 20
• 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 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 20
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
• 229940079322 interferon Drugs 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 239000000460 chlorine Substances 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
• 125000004432 carbon atom Chemical group C* 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims description 12
• 108091005804 Peptidases Proteins 0.000 claims description 12
• 239000004365 Protease Substances 0.000 claims description 12
• 229910052794 bromium Inorganic materials 0.000 claims description 12
• 125000001246 bromo group Chemical group Br* 0.000 claims description 12
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 12
• 229920002554 vinyl polymer Polymers 0.000 claims description 12
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 11
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 229920006395 saturated elastomer Polymers 0.000 claims description 10
• HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 9
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 9
• 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 208000015181 infectious disease Diseases 0.000 claims description 9
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 8
• 125000002837 carbocyclic group Chemical group 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 125000004122 cyclic group Chemical group 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 229940124683 HCV polymerase inhibitor Drugs 0.000 claims description 7
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 7
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 7
• 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 7
• 239000011737 fluorine Substances 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 229960000329 ribavirin Drugs 0.000 claims description 7
• HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 7
• 108060004795 Methyltransferase Proteins 0.000 claims description 6
• 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 6
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 230000002519 immonomodulatory effect Effects 0.000 claims description 6
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
• 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 claims description 4
• 208000010710 hepatitis C virus infection Diseases 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 239000002955 immunomodulating agent Substances 0.000 claims description 4
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000002950 monocyclic group Chemical group 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 230000029812 viral genome replication Effects 0.000 claims description 4
• 108010047761 Interferon-alpha Proteins 0.000 claims description 3
• 102000006992 Interferon-alpha Human genes 0.000 claims description 3
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims 3
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
• 239000005022 packaging material Substances 0.000 claims 2
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 13
• 208000036142 Viral infection Diseases 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 163
• 239000000243 solution Substances 0.000 description 149
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 86
• 238000006243 chemical reaction Methods 0.000 description 84
• 239000007787 solid Substances 0.000 description 80
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• 238000005481 NMR spectroscopy Methods 0.000 description 58
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
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