EA017556B1 - Пептидомиметические ингибиторы протеазы - Google Patents

Info

Publication number

EA017556B1

EA017556B1 EA200701869A EA200701869A EA017556B1 EA 017556 B1 EA017556 B1 EA 017556B1 EA 200701869 A EA200701869 A EA 200701869A EA 200701869 A EA200701869 A EA 200701869A EA 017556 B1 EA017556 B1 EA 017556B1

Authority

EA

Eurasian Patent Office

Prior art keywords

compound

group

optionally substituted

substituents

compound according

Prior art date

2000-08-31

Links

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• 239000000816 peptidomimetic Substances 0.000 title abstract description 13
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title abstract description 8
• 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 1084
• 238000000034 method Methods 0.000 claims abstract description 125
• 102000014150 Interferons Human genes 0.000 claims abstract description 56
• 108010050904 Interferons Proteins 0.000 claims abstract description 56
• 208000015181 infectious disease Diseases 0.000 claims abstract description 29
• 239000003001 serine protease inhibitor Substances 0.000 claims abstract description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
• 108091005804 Peptidases Proteins 0.000 claims abstract description 10
• 239000003937 drug carrier Substances 0.000 claims abstract description 10
• 239000004365 Protease Substances 0.000 claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
• 230000008569 process Effects 0.000 claims abstract description 6
• 230000004962 physiological condition Effects 0.000 claims abstract description 5
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract 2
• -1 cycloloxy Chemical group 0.000 claims description 278
• 125000001424 substituent group Chemical group 0.000 claims description 152
• 125000001931 aliphatic group Chemical group 0.000 claims description 114
• 125000003118 aryl group Chemical group 0.000 claims description 76
• 125000000217 alkyl group Chemical group 0.000 claims description 74
• 239000002253 acid Substances 0.000 claims description 73
• 125000001072 heteroaryl group Chemical group 0.000 claims description 63
• 150000003839 salts Chemical class 0.000 claims description 61
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 59
• 229910052757 nitrogen Inorganic materials 0.000 claims description 57
• 229920006395 saturated elastomer Polymers 0.000 claims description 52
• 239000001257 hydrogen Substances 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• 125000004122 cyclic group Chemical group 0.000 claims description 48
• 229940079322 interferon Drugs 0.000 claims description 45
• 125000004432 carbon atom Chemical group C* 0.000 claims description 44
• 238000006243 chemical reaction Methods 0.000 claims description 37
• 241000711549 Hepacivirus C Species 0.000 claims description 34
• 125000004429 atom Chemical group 0.000 claims description 34
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
• 230000000840 anti-viral effect Effects 0.000 claims description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims description 28
• 125000006239 protecting group Chemical group 0.000 claims description 28
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 27
• 239000002585 base Substances 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
• 238000011282 treatment Methods 0.000 claims description 24
• 150000001408 amides Chemical group 0.000 claims description 22
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 20
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 18
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
• 150000002431 hydrogen Chemical class 0.000 claims description 18
• 125000002252 acyl group Chemical group 0.000 claims description 17
• 230000015572 biosynthetic process Effects 0.000 claims description 17
• 125000002950 monocyclic group Chemical group 0.000 claims description 17
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 16
• 229940122055 Serine protease inhibitor Drugs 0.000 claims description 16
• 101710102218 Serine protease inhibitor Proteins 0.000 claims description 16
• 125000003435 aroyl group Chemical group 0.000 claims description 16
• 150000002466 imines Chemical class 0.000 claims description 16
• 239000012453 solvate Substances 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 125000003367 polycyclic group Chemical group 0.000 claims description 14
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 13
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 12
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 11
• 125000004104 aryloxy group Chemical group 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 11
• 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 9
• 108010047761 Interferon-alpha Proteins 0.000 claims description 9
• 102000006992 Interferon-alpha Human genes 0.000 claims description 9
• 125000004423 acyloxy group Chemical group 0.000 claims 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 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
• 125000005110 aryl thio group Chemical group 0.000 claims description 8
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
• 238000003776 cleavage reaction Methods 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 229960000329 ribavirin Drugs 0.000 claims description 8
• 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 8
• 230000007017 scission Effects 0.000 claims description 8
• 239000004471 Glycine Substances 0.000 claims description 7
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 7
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 7
• 238000011161 development Methods 0.000 claims description 7
• 150000004702 methyl esters Chemical class 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000006413 ring segment Chemical group 0.000 claims description 7
• 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
• 210000004027 cell Anatomy 0.000 claims description 6
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 6
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 6
• 239000002798 polar solvent Substances 0.000 claims description 6
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
• 238000007363 ring formation reaction Methods 0.000 claims description 6
• 230000029812 viral genome replication Effects 0.000 claims description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
• 229910052700 potassium Inorganic materials 0.000 claims description 5
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 5
• 241000596110 Biosteres Species 0.000 claims description 4
• 230000008878 coupling Effects 0.000 claims description 4
• 238000010168 coupling process Methods 0.000 claims description 4
• 238000005859 coupling reaction Methods 0.000 claims description 4
• LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 claims description 4
• 230000032050 esterification Effects 0.000 claims description 4
• 238000005886 esterification reaction Methods 0.000 claims description 4
• 229940124597 therapeutic agent Drugs 0.000 claims description 4
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000005150 heteroarylsulfinyl group Chemical group 0.000 claims description 3
• 229940126601 medicinal product Drugs 0.000 claims description 3
• 150000007530 organic bases Chemical class 0.000 claims description 3
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
• 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000005750 substituted cyclic group Chemical group 0.000 claims description 3
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 238000006957 Michael reaction Methods 0.000 claims description 2
• 125000005518 carboxamido group Chemical group 0.000 claims description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 229940079593 drug Drugs 0.000 claims description 2
• 150000003951 lactams Chemical group 0.000 claims description 2
• 230000004044 response Effects 0.000 claims description 2
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 102000040650 (ribonucleotides)n+m Human genes 0.000 claims 8
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 8
• UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims 4
• 102000000588 Interleukin-2 Human genes 0.000 claims 4
• 108010002350 Interleukin-2 Proteins 0.000 claims 4
• 102000004889 Interleukin-6 Human genes 0.000 claims 4
• 108090001005 Interleukin-6 Proteins 0.000 claims 4
• DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims 4
• 229960003805 amantadine Drugs 0.000 claims 4
• 150000001721 carbon Chemical group 0.000 claims 4
• 210000002443 helper t lymphocyte Anatomy 0.000 claims 4
• 229960002751 imiquimod Drugs 0.000 claims 4
• DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 claims 4
• 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 claims 4
• 108700027921 interferon tau Proteins 0.000 claims 4
• 229940100601 interleukin-6 Drugs 0.000 claims 4
• 229960000888 rimantadine Drugs 0.000 claims 4
• NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims 4
• 229960000707 tobramycin Drugs 0.000 claims 4
• 206010019799 Hepatitis viral Diseases 0.000 claims 3
• 102000013462 Interleukin-12 Human genes 0.000 claims 3
• 108010065805 Interleukin-12 Proteins 0.000 claims 3
• 229940117681 interleukin-12 Drugs 0.000 claims 3
• 208000010710 hepatitis C virus infection Diseases 0.000 claims 2
• 239000003444 phase transfer catalyst Substances 0.000 claims 2
• 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
• 241000700605 Viruses Species 0.000 claims 1
• 239000012445 acidic reagent Substances 0.000 claims 1
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims 1
• 230000001427 coherent effect Effects 0.000 claims 1
• PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 claims 1
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
• 208000006454 hepatitis Diseases 0.000 claims 1
• 231100000283 hepatitis Toxicity 0.000 claims 1
• 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 215
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• 230000000694 effects Effects 0.000 abstract description 29
• 238000002360 preparation method Methods 0.000 abstract description 25
• 229940047124 interferons Drugs 0.000 abstract description 11
• 230000000707 stereoselective effect Effects 0.000 abstract description 6
• 208000005176 Hepatitis C Diseases 0.000 abstract 1
• 101800001838 Serine protease/helicase NS3 Proteins 0.000 abstract 1
• 230000001747 exhibiting effect Effects 0.000 abstract 1
• 239000000243 solution Substances 0.000 description 298
• 239000011541 reaction mixture Substances 0.000 description 277
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 207
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 184
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 172
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 126
• 239000012267 brine Substances 0.000 description 125
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
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• 238000010898 silica gel chromatography Methods 0.000 description 56
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• 239000003153 chemical reaction reagent Substances 0.000 description 49
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
• 150000001413 amino acids Chemical class 0.000 description 43
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• 238000004587 chromatography analysis Methods 0.000 description 39
• 239000007858 starting material Substances 0.000 description 39
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 239000000047 product Substances 0.000 description 31
• 235000019441 ethanol Nutrition 0.000 description 29
• 239000000741 silica gel Substances 0.000 description 28
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
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• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 23
• 229910052717 sulfur Inorganic materials 0.000 description 22
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• 125000004434 sulfur atom Chemical group 0.000 description 16
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
• 125000003342 alkenyl group Chemical group 0.000 description 15
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• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 14
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• 101150016222 SNAT1 gene Proteins 0.000 description 13
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 238000001704 evaporation Methods 0.000 description 12
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• 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 11
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• 229910052745 lead Inorganic materials 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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• SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 9
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• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 8
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• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
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• 229910017976 MgO 4 Inorganic materials 0.000 description 6
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
• 239000004475 Arginine Substances 0.000 description 5
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
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