CA2752579A1 - Hepatitis c virus inhibitors - Google Patents

Info

Publication number

CA2752579A1

CA2752579A1 CA2752579A CA2752579A CA2752579A1 CA 2752579 A1 CA2752579 A1 CA 2752579A1 CA 2752579 A CA2752579 A CA 2752579A CA 2752579 A CA2752579 A CA 2752579A CA 2752579 A1 CA2752579 A1 CA 2752579A1

Authority

CA

Canada

Prior art keywords

pyrrolidinyl

benzimidazol

methyl

imidazol

phenylacetyl

Prior art date

2009-02-17

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 241000711549 Hepacivirus C Species 0.000 title abstract description 51
• 239000003112 inhibitor Substances 0.000 title description 37
• 239000000203 mixture Substances 0.000 claims abstract description 200
• 150000001875 compounds Chemical class 0.000 claims abstract description 157
• 238000000034 method Methods 0.000 claims abstract description 94
• 208000015181 infectious disease Diseases 0.000 claims abstract description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 77
• -1 (2S)-2-(8-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-1-pyrrolidinyl Chemical group 0.000 claims description 67
• 125000000217 alkyl group Chemical group 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 62
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 48
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 29
• 229940079322 interferon Drugs 0.000 claims description 26
• 108010050904 Interferons Proteins 0.000 claims description 24
• 102000014150 Interferons Human genes 0.000 claims description 24
• 125000005843 halogen group Chemical group 0.000 claims description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
• 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 18
• 229960000329 ribavirin Drugs 0.000 claims description 18
• 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 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 230000000694 effects Effects 0.000 claims description 17
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 16
• 101800001014 Non-structural protein 5A Proteins 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
• 108010047761 Interferon-alpha Proteins 0.000 claims description 8
• 102000006992 Interferon-alpha Human genes 0.000 claims description 8
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 6
• 101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 claims description 6
• 108060004795 Methyltransferase Proteins 0.000 claims description 6
• 108010022999 Serine Proteases Proteins 0.000 claims description 6
• 102000012479 Serine Proteases Human genes 0.000 claims description 6
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• 229910052760 oxygen Chemical group 0.000 claims description 6
• 108010006035 Metalloproteases Proteins 0.000 claims description 5
• 102000005741 Metalloproteases Human genes 0.000 claims description 5
• 101800001019 Non-structural protein 4B Proteins 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 238000011161 development Methods 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 239000001301 oxygen Chemical group 0.000 claims description 5
• 108020005544 Antisense RNA Proteins 0.000 claims description 4
• 229940124186 Dehydrogenase inhibitor Drugs 0.000 claims description 4
• HAEJPQIATWHALX-KQYNXXCUSA-N ITP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(N=CNC2=O)=C2N=C1 HAEJPQIATWHALX-KQYNXXCUSA-N 0.000 claims description 4
• 102100040018 Interferon alpha-2 Human genes 0.000 claims description 4
• 108010079944 Interferon-alpha2b Proteins 0.000 claims description 4
• 102000013462 Interleukin-12 Human genes 0.000 claims description 4
• 108010065805 Interleukin-12 Proteins 0.000 claims description 4
• 102000004889 Interleukin-6 Human genes 0.000 claims description 4
• 108090001005 Interleukin-6 Proteins 0.000 claims description 4
• 230000005867 T cell response Effects 0.000 claims description 4
• DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
• 229960003805 amantadine Drugs 0.000 claims description 4
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
• 239000003184 complementary RNA Substances 0.000 claims description 4
• 210000002443 helper t lymphocyte Anatomy 0.000 claims description 4
• 230000002452 interceptive effect Effects 0.000 claims description 4
• 108700027921 interferon tau Proteins 0.000 claims description 4
• 229940117681 interleukin-12 Drugs 0.000 claims description 4
• 229940100601 interleukin-6 Drugs 0.000 claims description 4
• UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 3
• 102000000588 Interleukin-2 Human genes 0.000 claims description 3
• 108010002350 Interleukin-2 Proteins 0.000 claims description 3
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
• 229960000888 rimantadine Drugs 0.000 claims description 3
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 8
• PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims 4
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 3
• RIMOHYAEDCMCNS-HUTISQBZSA-N (2r)-2-(diethylamino)-1-[(2r)-2-[7-[2-[(2s)-1-[(2r)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]-3h-benzo[e]benzimidazol-2-yl]pyrrolidin-1-yl]-2-phenylethanone Chemical compound C1([C@@H](N(CC)CC)C(=O)N2CCC[C@@H]2C=2NC=3C4=CC=C(C=C4C=CC=3N=2)C=2C=C3N=C(NC3=CC=2)[C@@H]2CCCN2C(=O)[C@H](N(CC)CC)C=2C=CC=CC=2)=CC=CC=C1 RIMOHYAEDCMCNS-HUTISQBZSA-N 0.000 claims 1
• VCAZJSQXGIMRDZ-SPUOKHKDSA-N (2r)-2-(diethylamino)-1-[(2s)-2-[4-[3-[2-[2-[(2s)-1-[(2r)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]ethynyl]phenyl]-1h-imidazol-5-yl]pyrrolidin-1-yl]-2-phenylethanone Chemical compound C1([C@@H](N(CC)CC)C(=O)N2CCC[C@H]2C=2N=CNC=2C=2C=CC=C(C=2)C#CC=2C=C3N=C(NC3=CC=2)[C@@H]2CCCN2C(=O)[C@H](N(CC)CC)C=2C=CC=CC=2)=CC=CC=C1 VCAZJSQXGIMRDZ-SPUOKHKDSA-N 0.000 claims 1
• YVBRVHHVXMEIRH-LZCGGXSTSA-N (2r)-2-(diethylamino)-1-[(2s)-2-[6-[2-[4-[2-[(2s)-1-[(2r)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-1h-imidazol-5-yl]phenyl]ethynyl]-1h-benzimidazol-2-yl]pyrrolidin-1-yl]-2-phenylethanone Chemical compound C1([C@@H](N(CC)CC)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C#CC2=CC=C(C=C2)C=2N=C(NC=2)[C@@H]2CCCN2C(=O)[C@H](N(CC)CC)C=2C=CC=CC=2)=CC=CC=C1 YVBRVHHVXMEIRH-LZCGGXSTSA-N 0.000 claims 1
• ICOHANMFASPHFD-IYTFMMMVSA-N (2r)-2-(diethylamino)-1-[(2s)-2-[6-[3-[2-[(2s)-1-[(2r)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-1h-imidazol-5-yl]phenyl]-1h-benzimidazol-2-yl]pyrrolidin-1-yl]-2-phenylethanone Chemical compound C1([C@@H](N(CC)CC)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C=2C=CC=C(C=2)C=2N=C(NC=2)[C@@H]2CCCN2C(=O)[C@H](N(CC)CC)C=2C=CC=CC=2)=CC=CC=C1 ICOHANMFASPHFD-IYTFMMMVSA-N 0.000 claims 1
• XSIMJIAOGYTKCF-IYTFMMMVSA-N (2r)-2-(diethylamino)-1-[(2s)-2-[6-[4-[2-[(2s)-1-[(2r)-2-(diethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-1h-imidazol-5-yl]phenyl]-1h-benzimidazol-2-yl]pyrrolidin-1-yl]-2-phenylethanone Chemical compound C1([C@@H](N(CC)CC)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C2=CC=C(C=C2)C=2N=C(NC=2)[C@@H]2CCCN2C(=O)[C@H](N(CC)CC)C=2C=CC=CC=2)=CC=CC=C1 XSIMJIAOGYTKCF-IYTFMMMVSA-N 0.000 claims 1
• NFKTWYIEHXZLLV-DFOKCWARSA-N (2r)-2-(dimethylamino)-n-[3-[5-[2-[(2s)-1-[(2r)-2-(dimethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]-1,3-oxazol-2-yl]phenyl]-2-phenylacetamide Chemical compound C1([C@@H](N(C)C)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C2=CN=C(O2)C=2C=CC=C(C=2)NC(=O)[C@H](N(C)C)C=2C=CC=CC=2)=CC=CC=C1 NFKTWYIEHXZLLV-DFOKCWARSA-N 0.000 claims 1
• FYMANEAIPMZKAM-JRTLPCBOSA-N (2r)-2-phenyl-1-[(2s)-2-[6-[4-[2-[2-[(2s)-1-[(2r)-2-phenyl-2-piperidin-1-ylacetyl]pyrrolidin-2-yl]-1h-imidazol-5-yl]ethynyl]phenyl]-1h-benzimidazol-2-yl]pyrrolidin-1-yl]-2-piperidin-1-ylethanone Chemical compound N1([C@@H](C(=O)N2[C@@H](CCC2)C=2NC=C(N=2)C#CC=2C=CC(=CC=2)C=2C=C3N=C(NC3=CC=2)[C@H]2N(CCC2)C(=O)[C@H](N2CCCCC2)C=2C=CC=CC=2)C=2C=CC=CC=2)CCCCC1 FYMANEAIPMZKAM-JRTLPCBOSA-N 0.000 claims 1
• JMLDVDRZTRRNHY-PXLJZGITSA-N (2s)-1-(2-phenylacetyl)-n-[3-[2-[2-[(2s)-1-(2-phenylacetyl)pyrrolidin-2-yl]-3h-benzimidazol-5-yl]-1,3-oxazol-5-yl]phenyl]pyrrolidine-2-carboxamide Chemical compound N1([C@@H](CCC1)C(=O)NC=1C=C(C=CC=1)C=1OC(=NC=1)C=1C=C2N=C(NC2=CC=1)[C@H]1N(CCC1)C(=O)CC=1C=CC=CC=1)C(=O)CC1=CC=CC=C1 JMLDVDRZTRRNHY-PXLJZGITSA-N 0.000 claims 1
• IZCGPYRQOMSTGW-ZPGRZCPFSA-N (2s)-1-(2-phenylacetyl)-n-[4-[2-[2-[(2s)-1-(2-phenylacetyl)pyrrolidin-2-yl]-3h-benzimidazol-5-yl]ethyl]phenyl]pyrrolidine-2-carboxamide Chemical compound N1([C@@H](CCC1)C(=O)NC=1C=CC(CCC=2C=C3NC(=NC3=CC=2)[C@H]2N(CCC2)C(=O)CC=2C=CC=CC=2)=CC=1)C(=O)CC1=CC=CC=C1 IZCGPYRQOMSTGW-ZPGRZCPFSA-N 0.000 claims 1
• HJAGWVHBOKXBAR-ZPGRZCPFSA-N (2s)-1-(2-phenylacetyl)-n-[4-[2-[2-[(2s)-1-(2-phenylacetyl)pyrrolidin-2-yl]-3h-benzimidazol-5-yl]ethynyl]phenyl]pyrrolidine-2-carboxamide Chemical compound N1([C@@H](CCC1)C(=O)NC=1C=CC(=CC=1)C#CC=1C=C2NC(=NC2=CC=1)[C@H]1N(CCC1)C(=O)CC=1C=CC=CC=1)C(=O)CC1=CC=CC=C1 HJAGWVHBOKXBAR-ZPGRZCPFSA-N 0.000 claims 1
• RLUNQFWBGWNCPU-JMNIVUANSA-N (2s)-1-[(2r)-2-(dimethylamino)-2-phenylacetyl]-n-[5-[5-[2-[(2s)-1-[(2r)-2-(dimethylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]-1,3-oxazol-2-yl]-2-methylphenyl]pyrrolidine-2-carboxamide Chemical compound C1([C@@H](N(C)C)C(=O)N2CCC[C@H]2C2=NC3=CC=C(C=C3N2)C2=CN=C(O2)C=2C=C(C(=CC=2)C)NC(=O)[C@@H]2CCCN2C(=O)[C@H](N(C)C)C=2C=CC=CC=2)=CC=CC=C1 RLUNQFWBGWNCPU-JMNIVUANSA-N 0.000 claims 1
• VPYPHRNGQLLTRN-CONSDPRKSA-N (2s)-1-acetyl-n-[4-[2-[2-[(2s)-1-(2-phenylacetyl)pyrrolidin-2-yl]-3h-benzimidazol-5-yl]ethyl]phenyl]pyrrolidine-2-carboxamide Chemical compound CC(=O)N1CCC[C@H]1C(=O)NC(C=C1)=CC=C1CCC1=CC=C(N=C(N2)[C@H]3N(CCC3)C(=O)CC=3C=CC=CC=3)C2=C1 VPYPHRNGQLLTRN-CONSDPRKSA-N 0.000 claims 1
• SNHCKLSBXJOYKR-CONSDPRKSA-N (2s)-1-acetyl-n-[4-[2-[2-[(2s)-1-(2-phenylacetyl)pyrrolidin-2-yl]-3h-benzimidazol-5-yl]ethynyl]phenyl]pyrrolidine-2-carboxamide Chemical compound CC(=O)N1CCC[C@H]1C(=O)NC1=CC=C(C#CC=2C=C3NC(=NC3=CC=2)[C@H]2N(CCC2)C(=O)CC=2C=CC=CC=2)C=C1 SNHCKLSBXJOYKR-CONSDPRKSA-N 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• RCCASXOCOJRZPA-CDBYGCFJSA-N methyl n-[(1r)-2-[(2s)-2-[5-[3-[2-[(2s)-1-[(2r)-2-(methoxycarbonylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]phenyl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C=2C=CC=C(C=2)C=2N=C(NC=2)[C@@H]2CCCN2C(=O)[C@H](NC(=O)OC)C=2C=CC=CC=2)=CC=CC=C1 RCCASXOCOJRZPA-CDBYGCFJSA-N 0.000 claims 1
• QXLFJWJLUQIKQX-CDBYGCFJSA-N methyl n-[(1r)-2-[(2s)-2-[5-[4-[2-[(2s)-1-[(2r)-2-(methoxycarbonylamino)-2-phenylacetyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]phenyl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2CCC[C@H]2C=2NC3=CC=C(C=C3N=2)C2=CC=C(C=C2)C=2N=C(NC=2)[C@@H]2CCCN2C(=O)[C@H](NC(=O)OC)C=2C=CC=CC=2)=CC=CC=C1 QXLFJWJLUQIKQX-CDBYGCFJSA-N 0.000 claims 1
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• 239000008194 pharmaceutical composition Substances 0.000 abstract description 15
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• 238000000746 purification Methods 0.000 description 40
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• 229910052740 iodine Inorganic materials 0.000 description 29
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
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