CA2557301A1

CA2557301A1 - Cyclobutenedione groups-containing compounds as inhibitors of hepatitis c virus ns3 serine protease

Cyclobutenedione groups-containing compounds as inhibitors of hepatitis c virus ns3 serine protease Download PDF

Info

Publication number: CA2557301A1
Authority: CA; Canada
Prior art keywords: compound; group; alkyl; hcv; compounds
Prior art date: 2004-02-27
Legal status : Abandoned

Application number

CA002557301A

Other languages

English (en)

French (fr)

Inventor

Stephane L. Bogen

Weidong Pan

Sumei Ruan

F. George Njoroge

Current Assignee

Merck Sharp and Dohme LLC

Original Assignee

Individual

Priority date

2004-02-27

Filing date

2005-02-24

Publication date

2005-09-15

2005-02-24 Application filed by Individual filed Critical Individual

2005-09-15 Publication of CA2557301A1 publication Critical patent/CA2557301A1/en

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 158
239000003112 inhibitor Substances 0.000 title description 22
108010022999 Serine Proteases Proteins 0.000 title description 12
102000012479 Serine Proteases Human genes 0.000 title description 12
RGBVWCQARBEPPW-UHFFFAOYSA-N cyclobut-3-ene-1,2-dione Chemical group O=C1C=CC1=O RGBVWCQARBEPPW-UHFFFAOYSA-N 0.000 title description 3
108700012707 hepatitis C virus NS3 Proteins 0.000 title 1
238000000034 method Methods 0.000 claims abstract description 75
108091005804 Peptidases Proteins 0.000 claims abstract description 27
239000004365 Protease Substances 0.000 claims abstract description 27
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
230000002401 inhibitory effect Effects 0.000 claims abstract description 7
102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract 8
241000711549 Hepacivirus C Species 0.000 claims description 74
-1 heteroalkenyl Chemical group 0.000 claims description 62
239000000203 mixture Substances 0.000 claims description 58
125000000217 alkyl group Chemical group 0.000 claims description 56
125000003118 aryl group Chemical group 0.000 claims description 34
150000003839 salts Chemical class 0.000 claims description 32
125000000753 cycloalkyl group Chemical group 0.000 claims description 30
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
125000001072 heteroaryl group Chemical group 0.000 claims description 27
125000000623 heterocyclic group Chemical group 0.000 claims description 27
108090000765 processed proteins & peptides Proteins 0.000 claims description 21
125000003710 aryl alkyl group Chemical group 0.000 claims description 19
229940079322 interferon Drugs 0.000 claims description 19
229910052760 oxygen Inorganic materials 0.000 claims description 19
239000012453 solvate Substances 0.000 claims description 19
125000000304 alkynyl group Chemical group 0.000 claims description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
150000002148 esters Chemical class 0.000 claims description 17
125000003342 alkenyl group Chemical group 0.000 claims description 16
229910052739 hydrogen Inorganic materials 0.000 claims description 16
238000011282 treatment Methods 0.000 claims description 16
239000003814 drug Substances 0.000 claims description 15
102000004196 processed proteins & peptides Human genes 0.000 claims description 15
229910052717 sulfur Inorganic materials 0.000 claims description 14
108010050904 Interferons Proteins 0.000 claims description 13
102000014150 Interferons Human genes 0.000 claims description 13
229920001184 polypeptide Polymers 0.000 claims description 11
208000005176 Hepatitis C Diseases 0.000 claims description 10
239000004480 active ingredient Substances 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
230000000694 effects Effects 0.000 claims description 9
125000004404 heteroalkyl group Chemical group 0.000 claims description 9
125000003545 alkoxy group Chemical group 0.000 claims description 7
125000002877 alkyl aryl group Chemical group 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
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 6
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
125000004414 alkyl thio group Chemical group 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
238000012545 processing Methods 0.000 claims description 6
208000024891 symptom Diseases 0.000 claims description 6
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
125000005110 aryl thio group Chemical group 0.000 claims description 5
125000004104 aryloxy group Chemical group 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
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 4
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
229960000329 ribavirin Drugs 0.000 claims description 4
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 4
125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 3
229910052794 bromium Inorganic materials 0.000 claims description 3
229910052801 chlorine Inorganic materials 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
101100240520 Caenorhabditis elegans nhr-14 gene Proteins 0.000 claims description 2
229930194542 Keto Natural products 0.000 claims description 2
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
125000003282 alkyl amino group Chemical group 0.000 claims description 2
125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 2
125000005281 alkyl ureido group Chemical group 0.000 claims description 2
125000003368 amide group Chemical group 0.000 claims description 2
125000001769 aryl amino group Chemical group 0.000 claims description 2
125000005421 aryl sulfonamido group Chemical group 0.000 claims description 2
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
125000005518 carboxamido group Chemical group 0.000 claims description 2
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
125000000468 ketone group Chemical group 0.000 claims description 2
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
239000003443 antiviral agent Substances 0.000 claims 4
125000001475 halogen functional group Chemical group 0.000 claims 2
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
230000001747 exhibiting effect Effects 0.000 claims 1
125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
238000007920 subcutaneous administration Methods 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
239000000243 solution Substances 0.000 description 91
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 55
239000000543 intermediate Substances 0.000 description 52
238000002360 preparation method Methods 0.000 description 52
235000019439 ethyl acetate Nutrition 0.000 description 49
238000006243 chemical reaction Methods 0.000 description 44
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
235000002639 sodium chloride Nutrition 0.000 description 40
239000012044 organic layer Substances 0.000 description 36
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
239000011541 reaction mixture Substances 0.000 description 31
229910052943 magnesium sulfate Inorganic materials 0.000 description 29
150000001412 amines Chemical class 0.000 description 28
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
239000012267 brine Substances 0.000 description 26
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
239000000047 product Substances 0.000 description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
238000000746 purification Methods 0.000 description 21
102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 20
125000004432 carbon atom Chemical group C* 0.000 description 20
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
239000007787 solid Substances 0.000 description 18
239000000758 substrate Substances 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
239000002253 acid Substances 0.000 description 17
229910052799 carbon Inorganic materials 0.000 description 17
239000003921 oil Substances 0.000 description 17
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
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101710144111 Non-structural protein 3 Proteins 0.000 description 16
229910052757 nitrogen Inorganic materials 0.000 description 16
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
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239000010410 layer Substances 0.000 description 13
230000002829 reductive effect Effects 0.000 description 13
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125000006413 ring segment Chemical group 0.000 description 10
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KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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235000001014 amino acid Nutrition 0.000 description 8
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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 8
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QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
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