TW201011030A - Tricyclic indole derivatives and methods of use thereof - Google Patents

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Publication number

TW201011030A

TW201011030A TW098119583A TW98119583A TW201011030A TW 201011030 A TW201011030 A TW 201011030A TW 098119583 A TW098119583 A TW 098119583A TW 98119583 A TW98119583 A TW 98119583A TW 201011030 A TW201011030 A TW 201011030A

Authority

TW

Taiwan

Prior art keywords

compound

doc

etoac

mmol

group

Prior art date

2008-06-13

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• 238000000034 method Methods 0.000 title claims abstract description 79
• 150000002475 indoles Chemical class 0.000 title abstract description 49
• 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 35
• 208000036142 Viral infection Diseases 0.000 claims abstract description 34
• 230000009385 viral infection Effects 0.000 claims abstract description 34
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
• 241000700605 Viruses Species 0.000 claims abstract description 23
• 150000001875 compounds Chemical class 0.000 claims description 330
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 114
• 150000003839 salts Chemical class 0.000 claims description 60
• 108010050904 Interferons Proteins 0.000 claims description 56
• 102000014150 Interferons Human genes 0.000 claims description 56
• -1 -NHCH3 Chemical group 0.000 claims description 53
• 125000000217 alkyl group Chemical group 0.000 claims description 47
• 239000003112 inhibitor Substances 0.000 claims description 47
• 229940079322 interferon Drugs 0.000 claims description 46
• 239000012453 solvate Substances 0.000 claims description 43
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 41
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 38
• 229940002612 prodrug Drugs 0.000 claims description 38
• 239000000651 prodrug Substances 0.000 claims description 38
• 239000003795 chemical substances by application Substances 0.000 claims description 31
• 238000011282 treatment Methods 0.000 claims description 31
• 230000003612 virological effect Effects 0.000 claims description 30
• 150000002148 esters Chemical class 0.000 claims description 28
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 28
• 239000003443 antiviral agent Substances 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 22
• 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 19
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound 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 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 19
• 229960000329 ribavirin Drugs 0.000 claims description 18
• 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 18
• 230000010076 replication Effects 0.000 claims description 15
• 208000015181 infectious disease Diseases 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 229940124683 HCV polymerase inhibitor Drugs 0.000 claims description 11
• 229940123627 Viral replication inhibitor Drugs 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
• 238000002844 melting Methods 0.000 claims description 10
• 230000008018 melting Effects 0.000 claims description 10
• 230000001419 dependent effect Effects 0.000 claims description 9
• 239000002777 nucleoside Substances 0.000 claims description 9
• 239000000126 substance Substances 0.000 claims description 9
• 229940122604 HCV protease inhibitor Drugs 0.000 claims description 7
• 230000000692 anti-sense effect Effects 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 7
• 125000000623 heterocyclic group Chemical group 0.000 claims description 7
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 7
• 229960002935 telaprevir Drugs 0.000 claims description 7
• BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 claims description 7
• 108010017101 telaprevir Proteins 0.000 claims description 7
• 229940021747 therapeutic vaccine Drugs 0.000 claims description 7
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 6
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
• 150000002923 oximes Chemical class 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 108010047761 Interferon-alpha Proteins 0.000 claims description 5
• 102000006992 Interferon-alpha Human genes 0.000 claims description 5
• 229940124691 antibody therapeutics Drugs 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 5
• 239000002532 enzyme inhibitor Substances 0.000 claims description 5
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• 229960000517 boceprevir Drugs 0.000 claims description 4
• LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical group O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 claims description 4
• 239000002955 immunomodulating agent Substances 0.000 claims description 4
• 229940121354 immunomodulator Drugs 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 150000003833 nucleoside derivatives Chemical class 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
• 229940118555 Viral entry inhibitor Drugs 0.000 claims description 3
• 125000003342 alkenyl group Chemical group 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 108010010648 interferon alfacon-1 Proteins 0.000 claims description 3
• 230000029812 viral genome replication Effects 0.000 claims description 3
• 210000002845 virion Anatomy 0.000 claims description 3
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
• 102100040018 Interferon alpha-2 Human genes 0.000 claims description 2
• 108010079944 Interferon-alpha2b Proteins 0.000 claims description 2
• 229940123066 Polymerase inhibitor Drugs 0.000 claims description 2
• 125000005577 anthracene group Chemical group 0.000 claims description 2
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
• 230000002584 immunomodulator Effects 0.000 claims description 2
• 229960003358 interferon alfacon-1 Drugs 0.000 claims description 2
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims description 2
• 125000001624 naphthyl group Chemical group 0.000 claims description 2
• 239000000203 mixture Substances 0.000 abstract description 132
• 230000003405 preventing effect Effects 0.000 abstract description 10
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 641
• 235000019439 ethyl acetate Nutrition 0.000 description 301
• 239000000243 solution Substances 0.000 description 146
• 238000003786 synthesis reaction Methods 0.000 description 121
• 230000015572 biosynthetic process Effects 0.000 description 108
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
• 239000011541 reaction mixture Substances 0.000 description 91
• 239000003814 drug Substances 0.000 description 87
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
• 238000006243 chemical reaction Methods 0.000 description 69
• 229940124597 therapeutic agent Drugs 0.000 description 69
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
• 238000002360 preparation method Methods 0.000 description 58
• 235000002639 sodium chloride Nutrition 0.000 description 53
• 238000012360 testing method Methods 0.000 description 47
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 44
• 239000012044 organic layer Substances 0.000 description 44
• 239000007787 solid Substances 0.000 description 44
• 238000005481 NMR spectroscopy Methods 0.000 description 42
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
• 239000000543 intermediate Substances 0.000 description 36
• 239000000047 product Substances 0.000 description 33
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 23
• 239000000725 suspension Substances 0.000 description 23
• 208000035475 disorder Diseases 0.000 description 22
• 238000005160 1H NMR spectroscopy Methods 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
• 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 19
• 239000012267 brine Substances 0.000 description 18
• 235000019341 magnesium sulphate Nutrition 0.000 description 18
• 238000000746 purification Methods 0.000 description 18
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
• 238000004458 analytical method Methods 0.000 description 15
• 229940047124 interferons Drugs 0.000 description 15
• 230000002829 reductive effect Effects 0.000 description 15
• 238000003756 stirring Methods 0.000 description 15
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 239000013078 crystal Substances 0.000 description 14
• 125000006413 ring segment Chemical group 0.000 description 14
• 229920006395 saturated elastomer Polymers 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• 102000004190 Enzymes Human genes 0.000 description 13
• 108090000790 Enzymes Proteins 0.000 description 13
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• 125000004432 carbon atom Chemical group C* 0.000 description 13
• 239000007858 starting material Substances 0.000 description 13
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
• 101710144111 Non-structural protein 3 Proteins 0.000 description 12
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• 230000000694 effects Effects 0.000 description 12
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 239000007789 gas Substances 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
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• 238000002648 combination therapy Methods 0.000 description 10
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• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
• 230000002265 prevention Effects 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
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• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
• 101800001014 Non-structural protein 5A Proteins 0.000 description 7
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• 238000004587 chromatography analysis Methods 0.000 description 6
• 230000007882 cirrhosis Effects 0.000 description 6
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