JP5345117B2 - Hcvns3プロテアーゼ阻害剤 - Google Patents
Hcvns3プロテアーゼ阻害剤 Download PDFInfo
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- JP5345117B2 JP5345117B2 JP2010227222A JP2010227222A JP5345117B2 JP 5345117 B2 JP5345117 B2 JP 5345117B2 JP 2010227222 A JP2010227222 A JP 2010227222A JP 2010227222 A JP2010227222 A JP 2010227222A JP 5345117 B2 JP5345117 B2 JP 5345117B2
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- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- carbonyl
- methyl
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- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 title description 6
- 208000015181 infectious disease Diseases 0.000 claims abstract description 29
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims abstract description 25
- -1 N (R 7 ) 2 Chemical group 0.000 claims description 158
- 150000001875 compounds Chemical class 0.000 claims description 142
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 105
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 125000003118 aryl group Chemical group 0.000 claims description 98
- 125000001072 heteroaryl group Chemical group 0.000 claims description 72
- 229910052757 nitrogen Inorganic materials 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000005842 heteroatom Chemical group 0.000 claims description 50
- 229910052760 oxygen Inorganic materials 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 125000005843 halogen group Chemical group 0.000 claims description 46
- 229910052717 sulfur Inorganic materials 0.000 claims description 46
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 238000002360 preparation method Methods 0.000 claims description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 239000003443 antiviral agent Substances 0.000 claims description 20
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 19
- 125000001624 naphthyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 13
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- 229940124772 HCV-NS5B polymerase inhibitor Drugs 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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- 239000004599 antimicrobial Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000002955 immunomodulating agent Substances 0.000 claims description 7
- 229940121354 immunomodulator Drugs 0.000 claims description 6
- 229940122604 HCV protease inhibitor Drugs 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000004419 alkynylene group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 241000711549 Hepacivirus C Species 0.000 abstract description 67
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 136
- 238000000034 method Methods 0.000 description 110
- 239000000243 solution Substances 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 86
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 68
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
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- 150000003839 salts Chemical class 0.000 description 27
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- NOTUPEVLPBDITL-SOWVLMPRSA-N [(1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]azanium;chloride Chemical compound Cl.C1CC1S(=O)(=O)NC(=O)[C@@]1(N)C[C@H]1C=C NOTUPEVLPBDITL-SOWVLMPRSA-N 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 229960004295 valine Drugs 0.000 description 15
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
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- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229950002810 valopicitabine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011991 zhan catalyst Substances 0.000 description 1
- 239000011992 zhan catalyst-1B Substances 0.000 description 1
Classifications
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- 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
- C07D487/12—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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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
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- 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
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- C07—ORGANIC CHEMISTRY
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- 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
- C07K5/0827—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
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
R1は、CO2R10、CONR10SO2R6、CONR10SO2NR8R9又はテトラゾリルであり;
R2は、C1−C6アルキル、C2−C6アルケニル又はC3−C8シクロアルキルであり(前記アルキル、アルケニル又はシクロアルキルは、1から3個のハロで場合によって置換されている。);
R3は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8)アルキル、アリール(C1−C8)アルキル又はHetであり(アリールは、フェニル又はナフチルであり、並びに前記アルキル、シクロアルキル又はアリールは、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から3個の置換基で場合によって置換されている。);
Hetは、N、O及びSから選択される1又は2個のヘテロ原子を有する5員から6員の飽和環状環であり(前記環は、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2から選択される1から3個の置換基で場合によって置換されている。);
R4は、H、C1−C8アルキル、C3−C8シクロアルキル(C1−C8)アルキル又はアリール(C1−C8)アルキルであり;アリールはフェニル又はナフチルであり、並びに前記アルキル、シクロアルキル又はアリールは、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から3個の置換基で場合によって置換されている。);
R5は、H、ハロ、OR10、C1−C6アルキル、CN、CF3、SR10、SO2(C1−C6アルキル)、C3−C8シクロアルキル、C3−C8シクロアルコキシ、C1−C6ハロアルキル、N(R7)2、アリール、ヘテロアリール又はヘテロシクリルであり;前記アリールは、フェニル又はナフチルであり、ヘテロアリールは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり、並びにヘテロシクリルは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり、並びに前記アリール、ヘテロアリール、ヘテロシクリル、シクロアルキル、シクロアルコキシ、アルキル又はアルコキシは、ハロ、OR10、SR10、N(R7)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、C3−C6シクロアルキル、C3−C6シクロアルコキシ、NO2、CN、CF3、SO2(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、S(O)(C1−C6アルキル)、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から4個の置換基で場合によって置換されており;前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの2つの隣接する置換基は、場合により一緒になって、両者で、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成し;
R6は、C1−C6アルキル、C3−C6シクロアルキル、C3−C6シクロアルキル(C1−C5)アルキル、アリール、アリール(C1−C4)アルキル、ヘテロアリール、ヘテロアリール(C1−C4アルキル)、ヘテロシクリル又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、1から2個のW置換基で場合によって置換されており;及び各アリールは、独立に、フェニル又はナフチルであり、各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;
Yは、C(=O)、SO2又はC(=N−CN)であり;
Zは、C(R10)2、O又はN(R4)であり;
Mは、C1−C12アルキレン又はC1−C12アルキニレンであり、前記アルキレン又はアルキニレンは、C1−C8アルキル、C3−C8シクロアルキル(C1−C8アルキル)及びアリール(C1−C8アルキル)からなる群から選択される1又は2個の置換基で場合によって置換されており;並びにMの中の隣接する2個の置換基は、場合により一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成し;
各R7は、独立に、H、C1−C6アルキル、C3−C6シクロアルキル、C3−C6シクロアルキル(C1−C5)アルキル、アリール、アリール(C1−C4)アルキル、ヘテロアリール、ヘテロアリール(C1−C4アルキル)、ヘテロシクリル又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、1から2個のW置換基で場合によって置換されており;及び各アリールは、独立に、フェニル又はナフチルであり、各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有し、5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有し、5から7員の飽和又は不飽和非芳香環であり;
各Wは、独立に、ハロ、OR10、C1−C6アルキル、CN、CF3、NO2、SR10、CO2R10、CON(R10)2、C(O)R10、N(R10)C(O)R10、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、C3−C8シクロアルキル、C3−C8シクロアルコキシ、C1−C6ハロアルキル、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、ハロ(C1−C6アルコキシ)、NR10SO2R10、SO2N(R10)2、NHCOOR10、NHCONHR10、アリール、ヘテロアリール又はヘテロシクリルであり;アリールは、フェニル又はナフチルであり、ヘテロアリールは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びにヘテロシクリルは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;
R8は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8アルキル)、アリール、アリール(C1−C4アルキル)、ヘテロアリール、ヘテロシクリル、ヘテロアリール(C1−C4アルキル)又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、アリール、C3−C8シクロアルキル、ヘテロアリール、ヘテロシクリル、C1−C6アルキル、ハロ(C1−C6アルコキシ)、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C(O)R10、C1−C6ハロアルキル、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10及びC(O)N(R10)2からなる群から選択される1から4個の置換基で場合によって置換されており;各アリールは、独立に、フェニル又はナフチルであり;各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;並びに前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの隣接する2個の置換基は、場合により一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成し;
R9は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8アルキル)、C1−C8アルコキシ、C3−C8シクロアルコキシ、アリール、アリール(C1−C4アルキル)、ヘテロアリール、ヘテロシクリル、ヘテロアリール(C1−C4アルキル)又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アルコキシ、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルは、アリール、C3−C8シクロアルキル、ヘテロアリール、ヘテロシクリル、C1−C6アルキル、ハロ(C1−C6アルコキシ)、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C(O)R10、C1−C6ハロアルキル、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10及びCON(R10)2からなる群から選択される1から4個の置換基で場合によって置換されており;各アリールは、独立に、フェニル又はナフチルであり;各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの隣接する2個の置換基は、場合により一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を場合によって形成し;
又はR8及びR9は、場合により一緒になって、これらが結合している窒素原子とともに、N、O及びSから選択される0から2個の追加のヘテロ原子を含有する4から8員の単環式環を形成し;並びに
各R10は、独立に、水素又はC1−C6アルキルである。)
本発明は、本発明の化合物を含有する医薬組成物及びこのような医薬組成物を調製する方法も含む。本発明は、HCV感染の1つ又はそれ以上の症候を治療又は予防する方法をさらに含む。
一般スキーム1及び一般スキーム2に概説されているとおりに、本発明の化合物を合成し得る。
BOP ベンゾトリアゾール−1−イル−オキシ−トリス−(ジメチルアミノ)−ホスホニウムヘキサフルオロホスファート
CH3CN アセトニトリル
DBU 1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン
DCC ジシクロヘキシルカルボジイミド
DCE ジクロロエタン
DCM ジクロメエタン
DIPEA ジイソプロピルエチルアミン
DMAP 4−ジメチルアミノピリジン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDC N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド
Et3N トリエチルアミン
Et2O ジエチルエーテル
EtOAc 酢酸エチル
EtOH エタノール
HATU O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート
HBr 臭化水素酸
HCl 塩酸
HOAc 酢酸
HOAt 1−ヒドロキシ−7−アザベンゾトリアゾール
LiOH 水酸化リチウム
MeOH メタノール
MgSO4 硫酸マグネシウム
MTBE メチルt−ブチルエーテル
Na2SO4 硫酸ナトリウム
NaHCO3 重炭酸ナトリウム
NaOH 水酸化ナトリウム
NH4Cl 塩化アンモニウム
NH4OH 水酸化アンモニウム
Pd/C パラジウム担持炭素
Pd(PPH3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
PhMe トルエン
PPh3 トリフェニルホスフィン
RT 室温
TBTU O−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート
THF テトラヒドロフラン
THF(2mL)、MeOH(0.5mL)及び水(1mL)中のメチル(5R,7S,10S)−10−ブチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキシラート(45mg、0.09mmol)の溶液へ、LiOH(21mg、0.87mmol)を添加した。反応混合物を40℃に加熱し、1時間攪拌して、その時点で、メチルエステル出発物質の完全消費をLC−MSにより観察した。その後、混合物を0.5N HCl及びEtOAcで後処理した。次いで、有機層をK2CO3上で乾燥させ、溶媒を真空蒸発した。粗生成物をDMF(1mL)中で取り出した。
ジクロロメタン(5mL)中の(5R,7S,10S)−10−tert−ブチル−15,15−ジメチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボン酸(100mg、0.19mmol)、(1R,2S)−1−{[(シクロプロピルスルホニル)アミノ]カルボニル}−2−ビニルシクロプロパンアミニウムクロリド(Llinas−Brunet et al US03/15755及びWang et al WO03/099274)(76mg、0.28mmol)、O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’−N’−テトラメチルウロニウムホスホラスヘキサフルオリド(HATU、108mg、0.28mmol)、DIPEA(0.073mL、0.42mmol)及び4−ジメチルアミノピリジン(2mg)の溶液を40℃で1時間攪拌した。反応溶液を飽和NaHCO3水溶液で希釈し、EtOAcで抽出した。混合したEtOAc層を水、塩水で洗浄し、Na2SO4上で乾燥させ、ろ過し、濃縮した。3%MeOH/CH2Cl2で溶出するフラッシュクロマトグラフィーにより残留物を精製し、(5R,7S,10S)−10−tert−ブチル−N−((1R,2S)−1−{[(シクロプロピルスルホニル)アミノ]カルボニル}−2−ビニルシクロプロピル)−15,15−ジメチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキサミド(80mg、収率57%)を得た。1H NMR(400MHz,ppm,DCl3)δ7.48(s,1H),7.23(s,1H),7.12(d,1H),6.23(d,J=15.9Hz,1H),5.94(m,1H),5.76(m,1H),5.50(m,2H),5.43(s,1H),5.24(d,J=16.6Hz,1H),5.11(d,1H),4.70(s,2H),4.61(d,1H),4.48(m,3H),4.35(d,1H),4.14(d,1H),3.74(d,1H),3.34(d,1H),2.89(m,1H),2.43(dd,2H),2.06(m,1H),1.93(m,1H),1.89(dd,1H),1.43(d,1H),1.25(m,3H),1.09(s,3H),1.06(s,9H),0.86(s,3H)。LRMS(ESI)m/z740[(M+H)+;C37H50N5O9Sに対する計算値:740]。
段階1:1−ブロモ−2,3−ビス(ブロモメチル)ベンゼン
DMF(50.9mL)中の(5R,7S,10S)−10−tert−ブチル−15,15−ジメチル−3,9,12−トリオキソ−6,7,9,10,11,12,14,15,16,17,18,19−ドデカヒドロ−1H,5H−2,23:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロヘンイコシン−7−カルボン酸(5.53g、10.17mmol)及び(1R,2R)−1−アミノ−N−(シクロプロピルスルホニル)−2−エチルシクロプロパンカルボキサミドヒドロクロリド(3.28g、12.21mmol)の溶液へ、DIPEA(7.11ml、40.7mmol)及びHATU(5.03g、13.22mmol)を添加した。完全な変換後(1時間)、反応混合物をEtOAc及び1N HCl間に分配した。有機層を塩水で三回洗浄し、MgSO4上で乾燥させ、溶媒を真空除去した。その後、粗製物質をシリカ上で精製し(勾配溶出、ヘキサン中の20から80%EtOAc)、表題化合物5.8gを白い粉末として生成した。
THF(2mL)及びMeOH(0.5mL)中のメチル(5R,7S,10S)−10−tert−ブチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16,17,18−ドデカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキシラート(90mg、0.18mmol)の溶液へ、LiOH(1N 1.75mL、1.75mmol)を添加した。反応混合物を40℃に加熱し、1時間攪拌して、その時点で、メチルエステルの出発物質の完全消費をLC−MSにより観察した。次いで、混合物を0.5N HCl及びEtOAcで後処理した。その後、有機層をK2CO3上で乾燥させ、溶媒を真空蒸発した。粗生成物をDMF(1mL)中で取り出した。
(5R,7S,10S)−10−tert−ブチル−N−((1R,2R)−1−{[(シクロプロピルスルホニル)アミノ]カルボニル}−2−エチルシクロプロピル)−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキサミド(III−16)
実施例17を実施例16に対し使用する方法に従って調製したが、メチル(5R,7S,10S)−10−tert−ブチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキシラート(実施例14、段階1)の代わりにメチル(5R,7S,10S)−10−tert−ブチル−3,9,12−トリオキソ−6,7,9,10,11,12,14,15,16,17−デカヒドロ−1H,5H−2,23:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロヘンイコシン−7−カルボキシラートを使用することは除く。1H NMR(500MHz,ppm,CD3OD)δ9.06(s,1H),7.27(t,1H),7.24(d,1H),7.18(d,1H),6.40(d,J=16.4Hz,1H),6.11(m,1H),5.39(t,1H),4.80(d,1H),4.69(m,4H),4.42(s,1H),4.25(d,1H),3.97(dd,1H),3.79(quin,1H),2.98(m,1H),2.50(q,1H),2.78(m,2H),2.15(m,1H),1.77−1.54(m,8H),1.32−1.19(m,4H),1.11(m,1H),1.07(s,9H),0.98(t,3H)。LRMS(ESI)m/z728[(M+H)+;C36H50N5O9Sに対する計算値:728]。
実施例18を実施例16に対し使用する方法に従って調製したが、メチル−(5R,7S,10S)−10−tert−ブチル−3,9,12−トリオキソ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキシラート(実施例14、段階1)の代わりにメチル(5R,7S,10S)−10−tert−ブチル−15,15−ジメチル−3,9,12−トリオキソ−6,7,9,10,11,12,14,15,16,17−デカヒドロ−1H,5H−2,23:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロヘンイコシン−7−カルボキシラートを使用することは除く。1H NMR(500MHz,ppm,CD3OD)δ10.05(s,1H),7.24(m,2H),7.17(d,1H),7.11(d,1H),6.61(s,1H),6.28(d,J=16.4Hz,1H),5.95(m,1H),5.58(m,1H),5.31(s,1H),4.71(m,2H),4.55(m,2H),4.46(d,2H),4.29(dd,1H),4.17(d,1H),3.89(d,1H),3.32(d,1H),2.92(m,1H),2.59(m,1H),2.21−2.30(m,2H),2.08(m,1H),1.60−1.78(m,6H),1.22−1.31(m,5H),1.06(s,9H),1.04(t,3H),0.093(t,3H),0.87(s,3H)。LRMS(ESI)m/z756[(M+H)+;C38H54N5O9Sに対する計算値:756]。
ジオキサン60mL中の2,2−ジメチルペント−4−エン−1−オール(2.24g、19.6mmol)及びトリホスゲン(2.56g、8.64mmol)の0℃の溶液へ、DIPEA(2.48g、19.2mmol)を添加した。生じた白い懸濁液を0℃で5分間攪拌し、次いで25℃に1時間にわたり温めた。懸濁液を氷浴で0℃に冷却し、続いて1N NaOH(19.2mL)及びL−tert−ブチルグリシン(2.52g、19.2mmol)を添加した。反応混合物を25℃に温め、72時間攪拌した。ジオキサンを真空除去し、反応混合物を1N NaOHでpH12に塩基性化した。水層をジクロロメタン(3×150mL)で抽出し、次いで6N HClでpHから1に酸性化した。水層をジクロロメタン(3×150mL)で抽出した。混合した有機層をMgSO4上で乾燥させ、濃縮し、N−{[(2,2−ジメチルペント−4−エニル)オキシ]カルボニル}−3−メチル−L−バリンを白い粉末(4.26g、収率827%)として得た。LRMS(ESI)m/z272[(M+H)+;C14H26NO4に対する計算値:272]。
0℃で窒素下において、無水14−ジオキサン(100mL)中の2,2−ジメチルヘキス−5−エン−1−オール(10.75g、83.85mmol)の攪拌した溶液へ、トリホスゲン(13.69g、46.12mmol)、次いでDIPEA(14.61mL、83.85mmol)を慎重に添加した。この反応溶液を22℃で1時間攪拌し、0℃に冷却して、1N NaOH(83.85mL、83.85mmol)及びL−tert−ロイシン(11.00g、83.85mmol)をゆっくりと添加して、その後22℃で20時間攪拌した。反応溶液を1N NaOHでpH10に塩基性化し、CH2Cl2(3×100mL)で洗浄して、1N HClでpH5に酸性化し、CH2Cl2(3×150mL)で抽出した。混合したCH2Cl2層を水(100mL)で洗浄し、Na2SO4上で乾燥させ、ろ過し、濃縮して、表題生成物(20.26g、84.66%)を得た。1H NMR(500MHz、CDCl3)δ5.85−5.77(m,1H);5.24(d,1H);5.01(d,1H);4.93(d,1H);4.20(d,1H);3.86(d,1H);3.79(d,1H);2.01(m,2H);1.36(m,2H);1.04(s,9H);0.92(m,6H)ppm。LRMS(ESI)m/z286[(M+H)+;C15H28NO4に対する計算値:286]。
テトラヒドロフラン(40mL)中のメチル3−メチル−N−{[メチル(ペント−4−エニル)アミノ]カルボニル}−L−バリナート(3.00g、11.2mmol)、水酸化リチウム(1M、56.0mL、56.0mmol)の溶液を50℃に1時間加熱した。反応フラスコの内容物を冷却し、蒸発して、テトラヒドロフランを除去した。残りの混合物を5%重硫酸カリウム中に注ぎ、塩化メチレン(3×100mL)で抽出した。混合した有機抽出物を無水硫酸ナトリウムで乾燥させ、ろ過し、蒸発して、表題化合物を無色の油状物2.87g(収率100%)として得た。LRMS(ESI)m/z257[(M+H)+;C13H25N2O3に対する計算値:257]。
段階1における4−ペンテノイルクロリドの代わりに5−ヘキセノイルクロリドを使用することにより、3−メチル−N−{[メチル(ヘキス−5−エニル)アミノ]カルボニル}−L−バリンを3−メチル−N−{[メチル(ペント−4−エニル)アミノ]カルボニル}−L−バリン(段階1から5)に対する方法に従って調製した。LRMS(ESI)m/z271[(M+H)+;C14H27N2O3に対する計算値:271]。
段階4におけるN−メチルペント−4−エン−1−アミンの代わりに2−メチルヘプト−6−エン−2−アミンを使用することにより、N−{[(1,1−ジメチルヘキス−5−エニル)アミノ]カルボニル}−3−メチル−L−バリンを3−メチル−N−{[メチル(ペント−4−エニル)アミノ]カルボニル}−L−バリン(段階4から5)に対する方法に従って調製した。
実施例13の代替的調製における段階10及び11で提供される方法に従い、段階11における(1R,2S)−1−{[(シクロプロピルスルホニル)アミノ]カルボニル}−2−ビニルシクロプロパンアミニウムクロリドを使用して、実施例41をメチル−(5R,7S,10S)−10−tert−ブチル−3,9,12−トリオキソ−17,18−ジデヒドロ−1,6,7,9,10,11,12,14,15,16−デカヒドロ−5H−2,22:5,8−ジメタノ−4,13,2,8,11−ベンゾジオキサトリアザシクロイコシン−7−カルボキシラートから調製した。1H NMR(400MHz,CDCl3,ppm)δ7.25−7.17(m,3H),7.09(br s,1H),5.80−5.71(m,1H),5.45(d,J=9.8Hz,1H),5.41(s,1H),5.23(d,J=17.2Hz,1H),5.13(d,J=9.6Hz,1H),4.82(m,3H),4.69−4.44(m,3H),4.38(m,2H),3.99(m,1H),3.81(dd,J=11.2,2.8Hz,1H),2.89(m,1H),2.80(s,1H),2.69−2.58(m,1H),2.53(m,1H),2.48(m,1H),2.33(m,1H),2.15−2,08(m,1H),1.94(t,J=5.9Hz,2H),1.83−1.75(m,1H),1.46(td,J=5.9,3.3Hz,1H),1.37(m,1H),1.06(s,9H)及び1.02(m,3H)。LRMS(ESI)m/z710.4[(M+H)+;C35H44N5O9Sに対する計算値:710.8]。
実施例43を2−ベンジル−4−ブロモ−7−フルオロイソインドリンから調製し、実施例3の段階3から6及び実施例13の代替的調製における段階7、8、10及び11に記載の方法を使用して、段階7における3−メチル−N−[(ペント−4−エニルオキシ)カルボニル]−L−バリン及び段階11における(1R,2S)−1−{[(シクロプロピル−スルホニル)アミノ]カルボニル}−2−ビニルシクロプロパンアミニウムクロリドを用いた。1H NMR(400MHz,CDCl3,ppm)δ9.86(s,1H),7.24(m,1H),7.20(m,1H),6.91(t,J=8.6Hz,1H),6.25(d,J=16.6Hz,1H),5.99−5.90(m,1H),5.78−5.64(m,1H),5.43(m,2H),5.25(d,J=16.6Hz,1H),5.15(d,J=10.3Hz,1H),4.74(m,2H),4.67(d,J=15.4Hz,1H),4.54(m,1H),4.47(t,J=8.8Hz,1H),4.39−4.31(m,2H),4.30−4.22(m,1H),3.88(m,1H),3.75(dd,1H),2.95−2.85(m,1H),2.50−2.39(m,2H),2.30−2.21(m,2H),2.15(m,1H),1.97−1.92(m,2H),1.72(m,1H),1.44(dd,J=9.7,5.8Hz,1H),1.31(m,2H)及び1.08(m,11H)。LRMS(ESI)m/z730.4[(M+H)+;C35H45FN5O9Sに対する計算値:730.8]。
実施例45を(3R,5S)−5−(メトキシカルボニル)ピロリジン−3−イル4−メトキシ−7−ビニル−1,3−ジヒドロ−2H−イソインドール−2−カルボキシラートヒドロクロリドから調製し、実施例13の代替的調製における段階7から11に記載の方法を使用し、段階7の3−メチル−N−[(ペント−4−エニルオキシ)カルボニル]−L−バリン及び段階11の(1R,2S)−1−{[(シクロプロピルスルホニル)アミノ]カルボニル}−2−ビニルシクロプロパンアミニウムクロリドを用いた。1H NMR(600MHz,DMSO−d6,ppm)δ10.46(s,1H),8.85(s,1H),7.10(d,J=8.3Hz,1H),7.06(d,J=8.0Hz,1H),6.85(d,J=8.5Hz,1H),5.63−5.54(m,1H),5.25(s,1H),5.22(d,J=18.2Hz,1H),5.10(d,J=11.8Hz,1H),4.64(d,J=14.2Hz,1H),4.56(d,J=13.5Hz,1H),4.52(d,J=13.5Hz,1H),4.50(d,J=14.2Hz,1H),4.33(dd,J=10.7Hz,6.8Hz,1H),4.23−4.18(m,2H),4.12−4.10(m,1H),3.78(s,3H),3.75−3.71(m,2H),2.96−2.90(m,1H),2.50(残留のDMSOにより不明瞭,1H),2.33−2.23(m,2H),2.18−2.11(m,1H),2.06−2.01(m,1H),1.71−1.69(m,1H),1.68−1.62(m,1H),1.53−1.43(m,3H),1.37−1.22(m,3H),1.10−1.07(m,2H),1.05−1.02(m,2H)及び1.00−0.86(m,9H)。LRMS(ESI)m/z744[(M+H)+;C36H50N5O10Sに対する計算値:744.3]。
実施例46を1−tert−ブチル2−メチル(2S,4R)−4−{[(8−ビニル−3,4−ジヒドロイソキノリン−2(1H)−イル)カルボニル]オキシ}ピロリジン−1,2−ジカルボキシラートから調製し、実施例3の段階6、続いて実施例13の代替的調製における段階7から11に記載の方法を使用した。1H NMR(400MHz,CDCl3,ppm)δ9.02(s,1H),7.13(m,1H),7.08(d,J=7.7Hz,1H),7.02(d,J=7.3Hz,1H),6.97(d,J=7.7Hz,1H),6.96(m,1H),5.36(s,1H),4.68(d,J=16.3Hz,1H),4.60−4.31(m,3H),4.25(m,1H),4.18(m,1H),4.11−3.94(m,2H),3.47(q,J=7.0Hz,2H),2.91(m,1H),2.80(m,2H),2.52(m,1H),2.41−2.28(m,2H),2.11(td,1H),1.60−1.52(m,3H),1.51(m,4H),1.32(m,3H),1.24(m,3H),1.21(t,J=7.0Hz,3H),1.09(m,2H),1.03(s,9H),0.93(s,3H)及び0.82(s,3H)。LRMS(ESI)m/z772.5[(M+H)+;C39H58N5O9Sに対する計算値:773.0]。
DCM(1200mL)中の上記における段階1からの生成物(92g、0.28mol)の溶液を0℃に冷却し、HClを10分間溶液に吹き込み、冷却浴を除去して、反応混合物を2時間攪拌した。窒素を5分間反応混合物に吹き込み、揮発物を蒸発した。残留物をDCM(×3)で共沸し、オフホワイトの粉末(75g)を得た。LRMS(M+H)+算出=233、検出233。
段階2におけるエチル2,2−ジメチルヘキス−5−エノアートの代わりにエチル1−ブト−3−エン−1−イルシクロプロパンカルボキシラートを使用することにより、N−{[(1−ブト−3−エン−1−イルシクロプロピル)メトキシ]カルボニル}−3−メチル−L−バリンをN−{[(2,2−ジメチルヘキス−5−エニル)オキシ]カルボニル}−3−メチル−L−バリン(段階2及び3)に対する方法に従って調製した。LRMS(ESI)m/z284.3[(M+H)+;C15H26NO4に対する計算値:284.2]。
t−ブチルグリシンの代わりに(2S)−アミノ(1−メチルシクロヘキシル)酢酸−HClを使用することにより、(2S)−(1−メチルシクロヘキシル){[(ペント−4−エン−1−イルオキシ)カルボニル]アミノ}酢酸を3−メチル−N−[(ペント−4−エニルオキシ)カルボニル]−L−バリンに対する方法に従って調製した。LRMS(ESI)m/z347.3[(M+Na+CH3CN)+;C17H28N2NaO4に対する計算値:347.2]。
水及びジオキサン1:1の混合物中におけるN−{[イソプロピル(ペント−4−エン−1−イル)アミノ]カルボニル}−3−メチル−L−バリナートの溶液(0.1M)へ、LiOH(4当量)を添加し、生じた混合物を室温で6時間攪拌した。次いで、反応混合物を減圧で濃縮し、粗残留物をEtOAc中で溶解した。有機相を水で洗浄した。水相をpH=2にして、EtOAcで再抽出した。Na2SO4上で乾燥させ、揮発物を蒸発した後、N−{[イソプロピル(ペント−4−エン−1−イル)アミノ]カルボニル}−3−メチル−L−バリンを茶色がかった固体(100%)として回収し、更なる精製を行わずして使用した。LRMS(ESI)m/z285[(M+H)+;C15H29N2O3に対する計算値:285.2]。
50mMHEPES、pH7.5、150mMNaCl、15%グリセロール、0.15%TritonX−100、10mMDTT及び0.1%PEG8000を含有する、最終容量が100μlのアッセイ緩衝液中で、NS3プロテアーゼのTRFアッセイを実行した。様々な濃度の阻害薬とともに、NS3プロテアーゼを、10から30分間、予め温置した。アッセイのペプチド基質は、Ac−C(Eu)−DDMEE−Abu−[COO]−XSAK(QSY7)−NH2であり、Euはユウロピウム標識グループであり、Abuは2−ヒドロキシプロパン酸(X)とのエステル結合を接続する1−アミノブタン酸である。NS3プロテアーゼ活性によるペプチドの加水分解は、蛍光体の消光物質からの分離に際して起こり、蛍光の増大をもたらす。プロテアーゼ活性は、TRFペプチド基質を添加することにより開始された(最終濃度50から100nM)。1時間後、室温で、pH5.5の500mM MES100μlを用いて、反応を消光した。50から400μsの遅延を伴う励起340nm、発光615nmにおいて、Victor V2又はFusion蛍光光度計(Perkin Elmer Life and Analytical Sciences)の何れかを使用して、生成物の蛍光を検出した。シグナル対バックグランド比10から30を用いて、異なる酵素型の試験濃度を選択した。阻害定数は、4パラメータフィットを用いて求めた。
Claims (20)
- 式(I)の化合物。
R1は、CO2R10、CONR10SO2R6、CONR10SO2NR8R9又はテトラゾリルであり;
R2は、C1−C6アルキル、C2−C6アルケニル又はC3−C8シクロアルキルであり(前記アルキル、アルケニル又はシクロアルキルは、未置換であるか又は1から3個のハロで置換されている。);
R3は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8)アルキル、アリール(C1−C8)アルキル又はHetであり(アリールは、フェニル又はナフチルであり、並びに前記アルキル、シクロアルキル又はアリールは、未置換であるか又はハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から3個の置換基で置換されている。);
Hetは、N、O及びSから選択される1又は2個のヘテロ原子を有する5員から6員の飽和環状環であり(前記環は、未置換であるか、又はハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2から選択される1から3個の置換基で置換されている。);
R4は、H、C1−C8アルキル、C3−C8シクロアルキル(C1−C8)アルキル又はアリール(C1−C8)アルキルであり;アリールはフェニル又はナフチルであり、並びに前記アルキル、シクロアルキル又はアリールは、未置換であるか又はハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から3個の置換基で置換されている。;
R5は、H、ハロ、OR10、C1−C6アルキル、CN、CF3、SR10、SO2(C1−C6アルキル)、C3−C8シクロアルキル、C3−C8シクロアルコキシ、C1−C6ハロアルキル、N(R7)2、アリール、ヘテロアリール又はヘテロシクリルであり;前記アリールは、フェニル又はナフチルであり、ヘテロアリールは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり、並びにヘテロシクリルは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり、並びに前記アリール、ヘテロアリール、ヘテロシクリル、シクロアルキル、シクロアルコキシ、アルキル又はアルコキシは、未置換であるか又はハロ、OR10、SR10、N(R7)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C1−C6ハロアルキル、ハロ(C1−C6アルコキシ)、C3−C6シクロアルキル、C3−C6シクロアルコキシ、NO2、CN、CF3、SO2(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、S(O)(C1−C6アルキル)、NHCOOR6、NHCOR6、NHCONHR6、CO2R10、C(O)R10及びCON(R10)2からなる群から選択される1から4個の置換基で置換されており;前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの2つの隣接する置換基は、一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成してもよく;
R6は、C1−C6アルキル、C3−C6シクロアルキル、C3−C6シクロアルキル(C1−C5)アルキル、アリール、アリール(C1−C4)アルキル、ヘテロアリール、ヘテロアリール(C1−C4アルキル)、ヘテロシクリル又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、未置換であるか又は1から2個のW置換基で置換されており;及び各アリールは、独立に、フェニル又はナフチルであり、各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;
Yは、C(=O)、SO2又はC(=N−CN)であり;
Zは、C(R10)2、O又はN(R4)であり;
Mは、C1−C12アルキレン又はC1−C12アルキニレンであり、前記アルキレン又はアルキニレンは、未置換であるか又はC1−C8アルキル、C3−C8シクロアルキル(C1−C8アルキル)及びアリール(C1−C8アルキル)からなる群から選択される1又は2個の置換基で置換されており;並びにMの中の隣接する2個の置換基は、一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成してもよく;
各R7は、独立に、H、C1−C6アルキル、C3−C6シクロアルキル、C3−C6シクロアルキル(C1−C5)アルキル、アリール、アリール(C1−C4)アルキル、ヘテロアリール、ヘテロアリール(C1−C4アルキル)、ヘテロシクリル又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、未置換であるか又は1から2個のW置換基で置換されており;及び各アリールは、独立に、フェニル又はナフチルであり、各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;
各Wは、独立に、ハロ、OR10、C1−C6アルキル、CN、CF3、NO2、SR10、CO2R10、CON(R10)2、C(O)R10、N(R10)C(O)R10、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、C3−C8シクロアルキル、C3−C8シクロアルコキシ、C1−C6ハロアルキル、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、ハロ(C1−C6アルコキシ)、NR10SO2R10、SO2N(R10)2、NHCOOR10、NHCONHR10、アリール、ヘテロアリール又はヘテロシクリルであり;アリールは、フェニル又はナフチルであり、ヘテロアリールは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びにヘテロシクリルは、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;
R8は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8アルキル)、アリール、アリール(C1−C4アルキル)、ヘテロアリール、ヘテロシクリル、ヘテロアリール(C1−C4アルキル)又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アリール、ヘテロアリール又はヘテロシクリルは、未置換であるか又はアリール、C3−C8シクロアルキル、ヘテロアリール、ヘテロシクリル、C1−C6アルキル、ハロ(C1−C6アルコキシ)、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C(O)R10、C1−C6ハロアルキル、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10及びC(O)N(R10)2からなる群から選択される1から4個の置換基で置換されており;各アリールは、独立に、フェニル又はナフチルであり;各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;並びに前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの隣接する2個の置換基は、一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成してもよく;
R9は、C1−C8アルキル、C3−C8シクロアルキル、C3−C8シクロアルキル(C1−C8アルキル)、C1−C8アルコキシ、C3−C8シクロアルコキシ、アリール、アリール(C1−C4アルキル)、ヘテロアリール、ヘテロシクリル、ヘテロアリール(C1−C4アルキル)又はヘテロシクリル(C1−C8アルキル)であり、前記アルキル、シクロアルキル、アルコキシ、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルは、未置換であるか又はアリール、C3−C8シクロアルキル、ヘテロアリール、ヘテロシクリル、C1−C6アルキル、ハロ(C1−C6アルコキシ)、ハロ、OR10、SR10、N(R10)2、N(C1−C6アルキル)O(C1−C6アルキル)、C1−C6アルキル、C(O)R10、C1−C6ハロアルキル、NO2、CN、CF3、SO2(C1−C6アルキル)、S(O)(C1−C6アルキル)、NR10SO2R6、SO2N(R6)2、NHCOOR6、NHCOR6、NHCONHR6、CO2R10及びCON(R10)2からなる群から選択される1から4個の置換基で置換されており;各アリールは、独立に、フェニル又はナフチルであり;各ヘテロアリールは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2又は3個のヘテロ原子を有する5員又は6員の芳香環であり;並びに各ヘテロシクリルは、独立に、N、O及びSから選択され、環炭素又は窒素を通じて結合された1、2、3又は4個のヘテロ原子を有する5から7員の飽和又は不飽和非芳香環であり;前記シクロアルキル、シクロアルコキシ、アリール、ヘテロアリール又はヘテロシクリルの隣接する2個の置換基は、一緒になって、N、O及びSから選択される0から3個のヘテロ原子を含有する3から6員の環状環を形成してもよく;
又はR8及びR9は、一緒になって、これらが結合している窒素原子とともに、N、O及びSから選択される0から2個の追加のヘテロ原子を含有する4から8員の単環式環を形成してもよく;並びに
各R10は、独立に、水素又はC1−C6アルキルであり、
但し、下記式:
の化合物は除く。) - R1がCO2R10、CONR10SO2R6又はCONHSO2NR8R9である、請求項2に記載の化合物。
- R1が、CONHSO2R6である、請求項3に記載の化合物。
- R1がCONHSO2R6であり、R6がC3−C8シクロアルキルである、請求項4に記載の化合物。
- R1がCONHSO2NR8R9であり、R8がC1−C3アルキルであり、及びR9がC1−C3アルキル又は−(CH2)1−2−フェニルである、請求項3に記載の化合物。
- R2が、C2−C4アルケニルである、請求項3に記載の化合物。
- R3が、未置換であるか又はC 1 −C 6 アルキルで置換されているC 5 −C 6 シクロアルキル、或いは、未置換であるか又はハロ及びOR 10 から選択される1から3個の置換基で置換されているC 1 −C 8 アルキルである、請求項7に記載の化合物。
- R5が、H、ハロ又はC1−C6アルコキシである、請求項8に記載の化合物。
- YがC=Oである、請求項9に記載の化合物。
- Zが、O、C(R10)2、NH又はN(C1−C8アルキル)である、請求項10に記載の化合物。
- Mが、置換されていないC4−C8アルキレン又は置換されていないC4−C8アルケニレンである、請求項11に記載の化合物。
- 請求項1から13の何れか1項に記載の化合物の有効量と、及び医薬として許容される担体とを含む医薬組成物。
- HCV抗ウイルス剤、免疫調節物質及び抗感染剤からなる群から選択される第二の治療剤をさらに含む、請求項14に記載の医薬組成物。
- HCV抗ウイルス剤がHCVプロテアーゼ阻害剤及びHCVNS5Bポリメラーゼ阻害剤からなる群から選択される抗ウイルス剤である、請求項15に記載の医薬組成物。
- HCVNS3プロテアーゼ活性を阻害することを必要としている対象においてHCVNS3プロテアーゼ活性を阻害するための医薬の調製における、請求項1から13の何れか1項に記載の化合物の使用。
- HCVによる感染を予防又は治療することを必要としている対象においてHCVによる感染を予防又は治療するための医薬の調製における、請求項1から13の何れか1項に記載の化合物の使用。
- 前記医薬が、HCV抗ウイルス剤、免疫調節物質、抗感染剤からなる群から選択される少なくとも1つの第二の治療剤をさらに含む、請求項18に記載の使用。
- HCV抗ウイルス剤がHCVプロテアーゼ阻害剤及びHCVNS5Bポリメラーゼ阻害剤からなる群から選択される抗ウイルス剤である、請求項19に記載の使用。
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