MXPA02010375A - Inhibidores macrociclicos de la ns3-serina proteasa del virus de la hepatitis c que comprenden porciones alquil y arilalanina p2. - Google Patents
Inhibidores macrociclicos de la ns3-serina proteasa del virus de la hepatitis c que comprenden porciones alquil y arilalanina p2.Info
- Publication number
- MXPA02010375A MXPA02010375A MXPA02010375A MXPA02010375A MXPA02010375A MX PA02010375 A MXPA02010375 A MX PA02010375A MX PA02010375 A MXPA02010375 A MX PA02010375A MX PA02010375 A MXPA02010375 A MX PA02010375A MX PA02010375 A MXPA02010375 A MX PA02010375A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- aryl
- mmol
- compound
- solution
- Prior art date
Links
- -1 aryl alanine Chemical compound 0.000 title claims description 101
- 125000000217 alkyl group Chemical group 0.000 title claims description 60
- 241000711549 Hepacivirus C Species 0.000 title description 40
- 235000004279 alanine Nutrition 0.000 title 1
- 239000003001 serine protease inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 108091005804 Peptidases Proteins 0.000 claims abstract description 25
- 239000004365 Protease Substances 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 150000002678 macrocyclic compounds Chemical class 0.000 claims abstract description 16
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract 5
- 239000000203 mixture Substances 0.000 claims description 63
- 239000000460 chlorine Substances 0.000 claims description 43
- 150000002148 esters Chemical class 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 28
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 17
- 239000004202 carbamide Substances 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 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 4
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 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
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229940079322 interferon Drugs 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 229940124530 sulfonamide Drugs 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 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
- 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
- 125000004422 alkyl sulphonamide 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
- 125000004421 aryl sulphonamide group Chemical group 0.000 claims description 2
- 125000004104 aryloxy 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
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 2
- 125000004475 heteroaralkyl group Chemical group 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
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 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 class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 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 group [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 group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000001544 thienyl group Chemical group 0.000 claims 2
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 101150113676 chr1 gene Proteins 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]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
- 125000005936 piperidyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 268
- 239000000243 solution Substances 0.000 description 203
- 239000011541 reaction mixture Substances 0.000 description 170
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 160
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- 239000007787 solid Substances 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
- 229910001868 water Inorganic materials 0.000 description 69
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 61
- 238000002360 preparation method Methods 0.000 description 61
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 239000012044 organic layer Substances 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 51
- 235000002639 sodium chloride Nutrition 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 238000000746 purification Methods 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 239000011780 sodium chloride Substances 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 238000004587 chromatography analysis Methods 0.000 description 42
- 239000011347 resin Substances 0.000 description 41
- 229920005989 resin Polymers 0.000 description 41
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 40
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 39
- 239000002253 acid Substances 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- 239000000047 product Substances 0.000 description 38
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000005859 coupling reaction Methods 0.000 description 33
- 239000010410 layer Substances 0.000 description 33
- 230000008878 coupling Effects 0.000 description 31
- 238000010168 coupling process Methods 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 229910052681 coesite Inorganic materials 0.000 description 30
- 229910052906 cristobalite Inorganic materials 0.000 description 30
- 229910052682 stishovite Inorganic materials 0.000 description 30
- 229910052905 tridymite Inorganic materials 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 27
- 239000000758 substrate Substances 0.000 description 27
- 235000012239 silicon dioxide Nutrition 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 24
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 150000001412 amines Chemical class 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- 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 20
- 239000011734 sodium Substances 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 19
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 19
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 101710144111 Non-structural protein 3 Proteins 0.000 description 16
- 108090000765 processed proteins & peptides Proteins 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
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- 210000004027 cell Anatomy 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N CD3OD Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
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- 238000003786 synthesis reaction Methods 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 239000007821 HATU Substances 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- 108010022999 Serine Proteases Proteins 0.000 description 11
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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 10
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- AVWQQPYHYQKEIZ-UHFFFAOYSA-K trisodium;2-dodecylbenzenesulfonate;3-dodecylbenzenesulfonate;4-dodecylbenzenesulfonate Chemical compound [Na+].[Na+].[Na+].CCCCCCCCCCCCC1=CC=C(S([O-])(=O)=O)C=C1.CCCCCCCCCCCCC1=CC=CC(S([O-])(=O)=O)=C1.CCCCCCCCCCCCC1=CC=CC=C1S([O-])(=O)=O AVWQQPYHYQKEIZ-UHFFFAOYSA-K 0.000 description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 7
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 7
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- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 6
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- FZRKAZHKEDOPNN-UHFFFAOYSA-N Nitric oxide anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
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- 229920001184 polypeptide Polymers 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 6
- 235000019345 sodium thiosulphate Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
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- VJPIOPZUQLPHRE-UHFFFAOYSA-N tert-butyl n-[2-(dimethylamino)-2-oxo-1-phenylethyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C(=O)N(C)C)C1=CC=CC=C1 VJPIOPZUQLPHRE-UHFFFAOYSA-N 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- 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)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Crystallography & Structural Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19820400P | 2000-04-19 | 2000-04-19 | |
| PCT/US2001/012530 WO2001081325A2 (en) | 2000-04-19 | 2001-04-17 | Macrocyclic ns3-serine protease inhibitors of hepatitis c virus comprising alkyl and aryl alanine p2 moieties |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA02010375A true MXPA02010375A (es) | 2003-04-25 |
Family
ID=22732422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MXPA02010375A MXPA02010375A (es) | 2000-04-19 | 2001-04-17 | Inhibidores macrociclicos de la ns3-serina proteasa del virus de la hepatitis c que comprenden porciones alquil y arilalanina p2. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6914122B2 (OSRAM) |
| EP (1) | EP1274724A2 (OSRAM) |
| JP (1) | JP4748912B2 (OSRAM) |
| KR (1) | KR20020097220A (OSRAM) |
| CN (3) | CN101580536A (OSRAM) |
| AR (1) | AR030558A1 (OSRAM) |
| AU (1) | AU2001253621A1 (OSRAM) |
| BR (1) | BR0110104A (OSRAM) |
| CA (1) | CA2406532A1 (OSRAM) |
| CZ (1) | CZ20023473A3 (OSRAM) |
| HK (1) | HK1048479A1 (OSRAM) |
| HU (1) | HUP0302957A2 (OSRAM) |
| IL (1) | IL151935A0 (OSRAM) |
| MX (1) | MXPA02010375A (OSRAM) |
| NO (1) | NO20025030L (OSRAM) |
| NZ (1) | NZ521456A (OSRAM) |
| PE (1) | PE20011288A1 (OSRAM) |
| PL (1) | PL358591A1 (OSRAM) |
| RU (1) | RU2002131163A (OSRAM) |
| SK (1) | SK14952002A3 (OSRAM) |
| WO (1) | WO2001081325A2 (OSRAM) |
| ZA (1) | ZA200208014B (OSRAM) |
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| US6323180B1 (en) | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
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-
2001
- 2001-04-17 PE PE2001000348A patent/PE20011288A1/es not_active Application Discontinuation
- 2001-04-17 PL PL01358591A patent/PL358591A1/xx not_active Application Discontinuation
- 2001-04-17 CN CNA2009100067369A patent/CN101580536A/zh active Pending
- 2001-04-17 JP JP2001578418A patent/JP4748912B2/ja not_active Expired - Fee Related
- 2001-04-17 AU AU2001253621A patent/AU2001253621A1/en not_active Abandoned
- 2001-04-17 CN CN01810566A patent/CN1432022A/zh active Pending
- 2001-04-17 HK HK03100478.8A patent/HK1048479A1/zh unknown
- 2001-04-17 BR BR0110104-8A patent/BR0110104A/pt not_active IP Right Cessation
- 2001-04-17 CA CA002406532A patent/CA2406532A1/en not_active Abandoned
- 2001-04-17 RU RU2002131163/04A patent/RU2002131163A/ru not_active Application Discontinuation
- 2001-04-17 NZ NZ521456A patent/NZ521456A/en unknown
- 2001-04-17 CN CNA2006101537103A patent/CN1935833A/zh active Pending
- 2001-04-17 SK SK1495-2002A patent/SK14952002A3/sk not_active Application Discontinuation
- 2001-04-17 KR KR1020027013965A patent/KR20020097220A/ko not_active Withdrawn
- 2001-04-17 CZ CZ20023473A patent/CZ20023473A3/cs unknown
- 2001-04-17 EP EP01927142A patent/EP1274724A2/en not_active Withdrawn
- 2001-04-17 AR ARP010101794A patent/AR030558A1/es unknown
- 2001-04-17 US US09/836,636 patent/US6914122B2/en not_active Expired - Fee Related
- 2001-04-17 WO PCT/US2001/012530 patent/WO2001081325A2/en not_active Ceased
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- 2001-04-17 MX MXPA02010375A patent/MXPA02010375A/es active IP Right Grant
- 2001-04-17 HU HU0302957A patent/HUP0302957A2/hu unknown
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2002
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- 2002-10-18 NO NO20025030A patent/NO20025030L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AR030558A1 (es) | 2003-08-27 |
| WO2001081325A3 (en) | 2002-08-01 |
| BR0110104A (pt) | 2003-01-07 |
| CN1432022A (zh) | 2003-07-23 |
| RU2002131163A (ru) | 2004-06-27 |
| CN101580536A (zh) | 2009-11-18 |
| CZ20023473A3 (cs) | 2003-01-15 |
| JP4748912B2 (ja) | 2011-08-17 |
| US6914122B2 (en) | 2005-07-05 |
| IL151935A0 (en) | 2003-04-10 |
| JP2003531199A (ja) | 2003-10-21 |
| NZ521456A (en) | 2004-07-30 |
| PE20011288A1 (es) | 2001-12-12 |
| KR20020097220A (ko) | 2002-12-31 |
| US20020016294A1 (en) | 2002-02-07 |
| CN1935833A (zh) | 2007-03-28 |
| EP1274724A2 (en) | 2003-01-15 |
| WO2001081325A2 (en) | 2001-11-01 |
| CA2406532A1 (en) | 2001-11-01 |
| NO20025030L (no) | 2002-12-18 |
| HUP0302957A2 (hu) | 2003-12-29 |
| AU2001253621A1 (en) | 2001-11-07 |
| ZA200208014B (en) | 2004-02-12 |
| HK1048479A1 (zh) | 2003-04-04 |
| NO20025030D0 (no) | 2002-10-18 |
| PL358591A1 (en) | 2004-08-09 |
| SK14952002A3 (sk) | 2003-03-04 |
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