TWI387603B - Ｈｃｖ ｎｓ３蛋白酶抑制劑 - Google Patents
Ｈｃｖ ｎｓ３蛋白酶抑制劑 Download PDFInfo
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- TWI387603B TWI387603B TW095125510A TW95125510A TWI387603B TW I387603 B TWI387603 B TW I387603B TW 095125510 A TW095125510 A TW 095125510A TW 95125510 A TW95125510 A TW 95125510A TW I387603 B TWI387603 B TW I387603B
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- Prior art keywords
- compound
- hcv
- carbonyl
- mmol
- methyl
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- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 121
- 150000003839 salts Chemical class 0.000 claims description 36
- 208000015181 infectious disease Diseases 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 239000003443 antiviral agent Substances 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000002947 alkylene group Chemical group 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 229940124772 HCV-NS5B polymerase inhibitor Drugs 0.000 claims description 9
- 229960005475 antiinfective agent Drugs 0.000 claims description 8
- 239000004599 antimicrobial Substances 0.000 claims description 8
- 230000002519 immonomodulatory effect Effects 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 229940122604 HCV protease inhibitor Drugs 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 184
- -1 alkali metal salt Chemical class 0.000 description 100
- 235000019439 ethyl acetate Nutrition 0.000 description 86
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 83
- 238000000034 method Methods 0.000 description 66
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 40
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 36
- 239000000203 mixture Substances 0.000 description 34
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
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- 239000012044 organic layer Substances 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 229960002429 proline Drugs 0.000 description 17
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
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- 239000011734 sodium Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
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- 239000007787 solid Substances 0.000 description 13
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 11
- 102000006992 Interferon-alpha Human genes 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 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 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229960000329 ribavirin Drugs 0.000 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 description 7
- 239000000725 suspension Substances 0.000 description 7
- NZXLPSMEGPPXHF-OCCSQVGLSA-N (2s,4r)-4-(4-ethenyl-1,3-dihydroisoindole-2-carbonyl)oxypyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)[C@H](C(=O)O)C[C@H]1OC(=O)N1CC2=C(C=C)C=CC=C2C1 NZXLPSMEGPPXHF-OCCSQVGLSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 101710111275 Non-structural 3 Proteins 0.000 description 6
- 239000012317 TBTU Substances 0.000 description 6
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- ASZRHSLOVXUBHJ-UHFFFAOYSA-N 1-bromo-2,3-bis(bromomethyl)benzene Chemical compound BrCC1=CC=CC(Br)=C1CBr ASZRHSLOVXUBHJ-UHFFFAOYSA-N 0.000 description 5
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- UIZVMOZAXAMASY-UHFFFAOYSA-N hex-5-en-1-ol Chemical compound OCCCCC=C UIZVMOZAXAMASY-UHFFFAOYSA-N 0.000 description 5
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- WXOFJAIJHIJPCS-JTQLQIEISA-N (2s)-2-(pent-4-enoxycarbonylamino)hexanoic acid Chemical compound CCCC[C@@H](C(O)=O)NC(=O)OCCCC=C WXOFJAIJHIJPCS-JTQLQIEISA-N 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
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- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
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- 229950006081 taribavirin Drugs 0.000 description 1
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- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
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- 108010072897 transcription factor Brn-2 Proteins 0.000 description 1
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/18—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
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| US70076405P | 2005-07-20 | 2005-07-20 | |
| US72456605P | 2005-10-07 | 2005-10-07 |
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| TW200740850A TW200740850A (en) | 2007-11-01 |
| TWI387603B true TWI387603B (zh) | 2013-03-01 |
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| TW095125510A TWI387603B (zh) | 2005-07-20 | 2006-07-12 | Ｈｃｖ ｎｓ３蛋白酶抑制劑 |
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| JP5406525B2 (ja) * | 2005-07-04 | 2014-02-05 | ツァナン・サイテック・カンパニー・リミテッド | ルテニウム錯体配位子、ルテニウム錯体、固定化ルテニウム錯体触媒及びその調製方法と用途 |
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| AU2006275605B2 (en) * | 2005-08-01 | 2011-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic peptides as HCV NS3 protease inhibitors |
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| GB0609492D0 (en) * | 2006-05-15 | 2006-06-21 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| GB0612423D0 (en) * | 2006-06-23 | 2006-08-02 | Angeletti P Ist Richerche Bio | Therapeutic agents |
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