NZ521456A - Macrocyclic NS3-Serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties - Google Patents

Info

Publication number

NZ521456A

NZ521456A NZ521456A NZ52145601A NZ521456A NZ 521456 A NZ521456 A NZ 521456A NZ 521456 A NZ521456 A NZ 521456A NZ 52145601 A NZ52145601 A NZ 52145601A NZ 521456 A NZ521456 A NZ 521456A

Authority

NZ

New Zealand

Prior art keywords

alkyl

aryl

compound

mmol

pct

Prior art date

2000-04-19

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• -1 aryl alanine Chemical compound 0.000 title claims description 104
• 125000000217 alkyl group Chemical group 0.000 title claims description 63
• 239000003001 serine protease inhibitor Substances 0.000 title claims description 4
• 241000711549 Hepacivirus C Species 0.000 title description 48
• 235000004279 alanine Nutrition 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 199
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 21
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 18
• 150000002678 macrocyclic compounds Chemical class 0.000 claims abstract description 17
• 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims abstract description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
• 238000011282 treatment Methods 0.000 claims abstract description 13
• 239000003814 drug Substances 0.000 claims abstract description 9
• 238000004519 manufacturing process Methods 0.000 claims abstract description 4
• 125000005842 heteroatom Chemical group 0.000 claims abstract 3
• 238000000034 method Methods 0.000 claims description 82
• 239000000203 mixture Substances 0.000 claims description 72
• 102100028701 General vesicular transport factor p115 Human genes 0.000 claims description 38
• 101000767151 Homo sapiens General vesicular transport factor p115 Proteins 0.000 claims description 38
• 150000002148 esters Chemical class 0.000 claims description 32
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 108091005804 Peptidases Proteins 0.000 claims description 30
• 239000004365 Protease Substances 0.000 claims description 30
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 30
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 101710144111 Non-structural protein 3 Proteins 0.000 claims description 23
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 239000004202 carbamide Substances 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 16
• 238000003776 cleavage reaction Methods 0.000 claims description 15
• 208000005176 Hepatitis C Diseases 0.000 claims description 14
• 230000007017 scission Effects 0.000 claims description 14
• 125000004432 carbon atom Chemical group C* 0.000 claims description 13
• 230000002401 inhibitory effect Effects 0.000 claims description 13
• 239000004480 active ingredient Substances 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
• 150000003839 salts Chemical class 0.000 claims description 10
• 102100020870 La-related protein 6 Human genes 0.000 claims description 9
• 108050008265 La-related protein 6 Proteins 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 150000001299 aldehydes Chemical class 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 239000012453 solvate Substances 0.000 claims description 7
• 125000005110 aryl thio group Chemical group 0.000 claims description 6
• 125000004104 aryloxy group Chemical group 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 6
• 150000002576 ketones Chemical class 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 238000006467 substitution reaction Methods 0.000 claims description 6
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 239000001301 oxygen Substances 0.000 claims description 5
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
• 101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• 150000001346 alkyl aryl ethers Chemical class 0.000 claims description 4
• 150000005215 alkyl ethers Chemical class 0.000 claims description 4
• 125000003368 amide group Chemical group 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 229940079322 interferon Drugs 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000004437 phosphorous atom Chemical group 0.000 claims description 4
• 229940124530 sulfonamide Drugs 0.000 claims description 4
• 239000011593 sulfur Substances 0.000 claims description 4
• RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
• 102000014150 Interferons Human genes 0.000 claims description 3
• 108010050904 Interferons Proteins 0.000 claims description 3
• 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 3
• 150000001408 amides Chemical class 0.000 claims description 3
• 230000001747 exhibiting effect Effects 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 229910052698 phosphorus Inorganic materials 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 150000007542 11-membered macrocycles Chemical class 0.000 claims description 2
• 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims description 2
• 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 2
• 229940100389 Sulfonylurea Drugs 0.000 claims description 2
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
• 150000003973 alkyl amines Chemical class 0.000 claims description 2
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
• 125000003282 alkyl amino group Chemical group 0.000 claims description 2
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 2
• 150000004789 alkyl aryl sulfoxides Chemical class 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
• 125000000304 alkynyl group Chemical group 0.000 claims description 2
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 2
• 125000001769 aryl amino group Chemical group 0.000 claims description 2
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
• 150000008378 aryl ethers Chemical class 0.000 claims description 2
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
• 125000005362 aryl sulfone group Chemical group 0.000 claims description 2
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
• 125000004421 aryl sulphonamide group Chemical group 0.000 claims description 2
• UZMZVDOOVXLRID-UHFFFAOYSA-N azanylidyne-(nitrosulfonylamino)methane Chemical compound [O-][N+](=O)S(=O)(=O)NC#N UZMZVDOOVXLRID-UHFFFAOYSA-N 0.000 claims description 2
• OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 2
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 2
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
• LGAILEFNHXWAJP-BMEPFDOTSA-N macrocycle Chemical group N([C@H]1[C@@H](C)CC)C(=O)C(N=2)=CSC=2CNC(=O)C(=C(O2)C)N=C2[C@H]([C@@H](C)CC)NC(=O)C2=CSC1=N2 LGAILEFNHXWAJP-BMEPFDOTSA-N 0.000 claims description 2
• 229960000329 ribavirin Drugs 0.000 claims description 2
• 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 2
• 150000003457 sulfones Chemical class 0.000 claims description 2
• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
• 150000003462 sulfoxides Chemical class 0.000 claims description 2
• 238000012360 testing method Methods 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
• 239000003443 antiviral agent Substances 0.000 claims 2
• 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
• 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
• 125000001544 thienyl group Chemical class 0.000 claims 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
• 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
• 150000002825 nitriles Chemical class 0.000 claims 1
• MGQNMYSRDBFUIR-UHFFFAOYSA-N nitro cyanoformate Chemical compound [O-][N+](=O)OC(=O)C#N MGQNMYSRDBFUIR-UHFFFAOYSA-N 0.000 claims 1
• 125000004076 pyridyl group Chemical group 0.000 claims 1
• 208000035475 disorder Diseases 0.000 abstract description 5
• 125000006413 ring segment Chemical group 0.000 abstract 1
• 239000000243 solution Substances 0.000 description 201
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 190
• 239000011541 reaction mixture Substances 0.000 description 176
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
• 239000007787 solid Substances 0.000 description 81
• 229910001868 water Inorganic materials 0.000 description 77
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• 238000002360 preparation method Methods 0.000 description 61
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 59
• 239000012044 organic layer Substances 0.000 description 57
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 52
• 238000000746 purification Methods 0.000 description 50
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
• 239000012267 brine Substances 0.000 description 42
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 41
• 238000004587 chromatography analysis Methods 0.000 description 41
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• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 39
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 39
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• 230000008878 coupling Effects 0.000 description 27
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• 239000000758 substrate Substances 0.000 description 27
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• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 22
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
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