ZA200607215B - HCV NS-3 serine protease inhibitors - Google Patents

Info

Publication number

ZA200607215B

ZA200607215B ZA200607215A ZA200607215A ZA200607215B ZA 200607215 B ZA200607215 B ZA 200607215B ZA 200607215 A ZA200607215 A ZA 200607215A ZA 200607215 A ZA200607215 A ZA 200607215A ZA 200607215 B ZA200607215 B ZA 200607215B

Authority

ZA

South Africa

Prior art keywords

compound according

amino

optionally substituted

substituted

cealkyl

Prior art date

2004-01-30

Links

• Espacenet
• Global Dossier
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• 239000003001 serine protease inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 205
• -1 Y-NHSO Inorganic materials 0.000 claims description 182
• 125000000217 alkyl group Chemical group 0.000 claims description 55
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 49
• 125000005843 halogen group Chemical group 0.000 claims description 48
• 239000000203 mixture Substances 0.000 claims description 41
• 229910052701 rubidium Inorganic materials 0.000 claims description 33
• 125000003118 aryl group Chemical group 0.000 claims description 30
• 125000001072 heteroaryl group Chemical group 0.000 claims description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims description 30
• 229910003827 NRaRb Inorganic materials 0.000 claims description 28
• 150000001408 amides Chemical class 0.000 claims description 26
• 125000003368 amide group Chemical group 0.000 claims description 25
• 229910052799 carbon Inorganic materials 0.000 claims description 25
• 150000002678 macrocyclic compounds Chemical class 0.000 claims description 25
• 238000011282 treatment Methods 0.000 claims description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 229920006395 saturated elastomer Polymers 0.000 claims description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 125000004122 cyclic group Chemical group 0.000 claims description 14
• 125000005842 heteroatom Chemical group 0.000 claims description 14
• 239000003112 inhibitor Substances 0.000 claims description 14
• 125000004043 oxo group Chemical group O=* 0.000 claims description 13
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• 125000002947 alkylene group Chemical group 0.000 claims description 11
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 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 description 10
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
• 230000000840 anti-viral effect Effects 0.000 claims description 9
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 9
• 150000002825 nitriles Chemical group 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 150000003839 salts Chemical class 0.000 claims description 9
• 125000004432 carbon atom Chemical group C* 0.000 claims description 8
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 239000000651 prodrug Substances 0.000 claims description 8
• 229940002612 prodrug Drugs 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 7
• 125000006413 ring segment Chemical group 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 6
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 239000001257 hydrogen Substances 0.000 claims description 5
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 238000011321 prophylaxis Methods 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• 229910052792 caesium Inorganic materials 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• KMGCKSAIIHOKCX-UHFFFAOYSA-N 2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2CC(O)CC2=C1 KMGCKSAIIHOKCX-UHFFFAOYSA-N 0.000 claims description 3
• 206010054261 Flavivirus infection Diseases 0.000 claims description 3
• 102000014150 Interferons Human genes 0.000 claims description 3
• 108010050904 Interferons Proteins 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
• 229920002554 vinyl polymer Polymers 0.000 claims description 3
• 125000006083 1-bromoethyl group Chemical group 0.000 claims description 2
• 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 2
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
• 125000005999 2-bromoethyl group Chemical group 0.000 claims description 2
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
• 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 2
• 125000003342 alkenyl group Chemical group 0.000 claims description 2
• 125000003282 alkyl amino group Chemical group 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000001188 haloalkyl group Chemical group 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 229940127073 nucleoside analogue Drugs 0.000 claims description 2
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 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
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
• 229940079322 interferon Drugs 0.000 claims 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• 238000002360 preparation method Methods 0.000 description 79
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
• 238000006243 chemical reaction Methods 0.000 description 51
• 238000000034 method Methods 0.000 description 48
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• 150000001413 amino acids Chemical class 0.000 description 41
• 238000004128 high performance liquid chromatography Methods 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
• 229940024606 amino acid Drugs 0.000 description 35
• 235000001014 amino acid Nutrition 0.000 description 35
• 239000000243 solution Substances 0.000 description 35
• 238000005859 coupling reaction Methods 0.000 description 34
• 230000008878 coupling Effects 0.000 description 31
• 238000010168 coupling process Methods 0.000 description 31
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
• 230000015572 biosynthetic process Effects 0.000 description 24
• 150000002148 esters Chemical group 0.000 description 24
• 239000011347 resin Substances 0.000 description 23
• 229920005989 resin Polymers 0.000 description 23
• 150000001412 amines Chemical class 0.000 description 22
• VNUIKDVHZMWBTI-UHFFFAOYSA-N chloro carbamate Chemical compound NC(=O)OCl VNUIKDVHZMWBTI-UHFFFAOYSA-N 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 125000006239 protecting group Chemical group 0.000 description 21
• 239000002904 solvent Substances 0.000 description 21
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
• 239000002253 acid Substances 0.000 description 20
• 238000000746 purification Methods 0.000 description 20
• 239000002585 base Substances 0.000 description 19
• 239000007787 solid Substances 0.000 description 19
• ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 18
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
• 229940126142 compound 16 Drugs 0.000 description 18
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
• 235000019439 ethyl acetate Nutrition 0.000 description 17
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 16
• 238000003786 synthesis reaction Methods 0.000 description 16
• 229910001868 water Inorganic materials 0.000 description 16
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• 239000012634 fragment Substances 0.000 description 15
• 108090000765 processed proteins & peptides Proteins 0.000 description 15
• 229940079593 drug Drugs 0.000 description 13
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
• 239000013543 active substance Substances 0.000 description 11
• 230000036961 partial effect Effects 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 10
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
• 239000007822 coupling agent Substances 0.000 description 10
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• 238000003818 flash chromatography Methods 0.000 description 9
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
• 239000007821 HATU Substances 0.000 description 8
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• 150000001540 azides Chemical class 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 239000003826 tablet Substances 0.000 description 8
• 150000008575 L-amino acids Chemical class 0.000 description 7
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
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• 150000001299 aldehydes Chemical class 0.000 description 7
• 150000002429 hydrazines Chemical class 0.000 description 7
• 239000012074 organic phase Substances 0.000 description 7
• 239000002243 precursor Substances 0.000 description 7
• 239000000047 product Substances 0.000 description 7
• 125000004076 pyridyl group Chemical group 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 235000002639 sodium chloride Nutrition 0.000 description 7
• LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 description 6
• OUCUOMVLTQBZCY-BYPYZUCNSA-N (2s)-1-azaniumylpyrrolidine-2-carboxylate Chemical class NN1CCC[C@H]1C(O)=O OUCUOMVLTQBZCY-BYPYZUCNSA-N 0.000 description 6
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
• 238000005160 1H NMR spectroscopy Methods 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• 102100029571 Immunoglobulin J chain Human genes 0.000 description 6
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• 230000002378 acidificating effect Effects 0.000 description 6
• 239000002168 alkylating agent Substances 0.000 description 6
• 229940100198 alkylating agent Drugs 0.000 description 6
• 238000010511 deprotection reaction Methods 0.000 description 6
• 150000002170 ethers Chemical class 0.000 description 6
• ABLGTTUCCPCVGX-NSHDSACASA-N methyl (2s)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)C1CCCCC1 ABLGTTUCCPCVGX-NSHDSACASA-N 0.000 description 6
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• OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical class NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 6
• 150000003147 proline derivatives Chemical class 0.000 description 6
• 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 6
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• 238000006268 reductive amination reaction Methods 0.000 description 6
• 238000010561 standard procedure Methods 0.000 description 6
• FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 6
• 229940124530 sulfonamide Drugs 0.000 description 6
• SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 5
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• TYSWVSHEZSSWTE-UHFFFAOYSA-N 2-amino-n-(2-hydroxy-2,3-dihydro-1h-inden-1-yl)-3,3-dimethylbutanamide Chemical compound C1=CC=C2C(NC(=O)C(N)C(C)(C)C)C(O)CC2=C1 TYSWVSHEZSSWTE-UHFFFAOYSA-N 0.000 description 5
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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• 102000012479 Serine Proteases Human genes 0.000 description 5
• 108010022999 Serine Proteases Proteins 0.000 description 5
• 125000003277 amino group Chemical group 0.000 description 5
• 239000003443 antiviral agent Substances 0.000 description 5
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• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
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• 125000005647 linker group Chemical group 0.000 description 5
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• 125000004193 piperazinyl group Chemical group 0.000 description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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• 125000003831 tetrazolyl group Chemical group 0.000 description 5
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
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