AU2006319716B2 - Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation - Google Patents
Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation Download PDFInfo
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- AU2006319716B2 AU2006319716B2 AU2006319716A AU2006319716A AU2006319716B2 AU 2006319716 B2 AU2006319716 B2 AU 2006319716B2 AU 2006319716 A AU2006319716 A AU 2006319716A AU 2006319716 A AU2006319716 A AU 2006319716A AU 2006319716 B2 AU2006319716 B2 AU 2006319716B2
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- 238000000034 method Methods 0.000 title claims abstract description 77
- 230000008569 process Effects 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims description 47
- 239000004472 Lysine Substances 0.000 title abstract description 16
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 title abstract description 16
- 239000003696 aspartic proteinase inhibitor Substances 0.000 title description 6
- 229940002612 prodrug Drugs 0.000 title description 4
- 239000000651 prodrug Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 269
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 72
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 45
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 186
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- -1 methylenedioxy group Chemical group 0.000 claims description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 88
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 86
- 239000000243 solution Substances 0.000 claims description 62
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 41
- 150000001413 amino acids Chemical class 0.000 claims description 36
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- 229910052801 chlorine Inorganic materials 0.000 claims description 31
- 229910052740 iodine Inorganic materials 0.000 claims description 31
- 239000008346 aqueous phase Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 19
- 239000011734 sodium Substances 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 17
- 229910019142 PO4 Inorganic materials 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 16
- 239000010452 phosphate Substances 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 13
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 229920000137 polyphosphoric acid Chemical class 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 7
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical class OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229920000685 trimethylsilyl polyphosphate Polymers 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 230000000865 phosphorylative effect Effects 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 56
- 239000000543 intermediate Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 239000000203 mixture Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 28
- 229940024606 amino acid Drugs 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 26
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- 241000725303 Human immunodeficiency virus Species 0.000 description 20
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 18
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- UDPHXXOODGNDCG-UHFFFAOYSA-N [6-amino-2-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]hexyl] dihydrogen phosphate Chemical compound NCCCCC(COP(O)(O)=O)N(CC(C)C)S(=O)(=O)C1=CC=C(N)C=C1 UDPHXXOODGNDCG-UHFFFAOYSA-N 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- QAHLFXYLXBBCPS-IZEXYCQBSA-N methyl n-[(2s)-1-[[(5s)-5-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-6-hydroxyhexyl]amino]-1-oxo-3,3-diphenylpropan-2-yl]carbamate Chemical compound C=1C=CC=CC=1C([C@H](NC(=O)OC)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)C1=CC=CC=C1 QAHLFXYLXBBCPS-IZEXYCQBSA-N 0.000 description 15
- 235000021317 phosphate Nutrition 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 14
- 235000018977 lysine Nutrition 0.000 description 14
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 14
- 238000011282 treatment Methods 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
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- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
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- SCWIUHICGSPBKM-VIFPVBQESA-N (3s)-3-(2-methylpropylamino)azepan-2-one Chemical compound CC(C)CN[C@H]1CCCCNC1=O SCWIUHICGSPBKM-VIFPVBQESA-N 0.000 description 7
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
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- KHASNRBNVBIREH-UHFFFAOYSA-N methyl n-[1-[[5-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-6-phosphonooxyhexyl]amino]-1-oxo-3,3-diphenylpropan-2-yl]carbamate Chemical compound C=1C=C(N)C=CC=1S(=O)(=O)N(CC(C)C)C(COP(O)(O)=O)CCCCNC(=O)C(NC(=O)OC)C(C=1C=CC=CC=1)C1=CC=CC=C1 KHASNRBNVBIREH-UHFFFAOYSA-N 0.000 description 1
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- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- XRTYMJYAOZHUHI-UHFFFAOYSA-N n-(2-methylpropyl)benzenesulfonamide Chemical compound CC(C)CNS(=O)(=O)C1=CC=CC=C1 XRTYMJYAOZHUHI-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- OFYAYGJCPXRNBL-LBPRGKRZSA-N naphthalen-2-yl-3-alanine Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-LBPRGKRZSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 1
- 229960001624 pentamidine isethionate Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 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 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- YFNGWGVTFYSJHE-UHFFFAOYSA-K trisodium;phosphonoformate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O YFNGWGVTFYSJHE-UHFFFAOYSA-K 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000024275 uncoating of virus Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74064205P | 2005-11-30 | 2005-11-30 | |
| US60/740,642 | 2005-11-30 | ||
| PCT/CA2006/001963 WO2007062526A1 (en) | 2005-11-30 | 2006-11-30 | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
Publications (2)
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|---|---|
| AU2006319716A1 AU2006319716A1 (en) | 2007-06-07 |
| AU2006319716B2 true AU2006319716B2 (en) | 2012-02-02 |
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|---|---|---|---|
| AU2006319716A Ceased AU2006319716B2 (en) | 2005-11-30 | 2006-11-30 | Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation |
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| US (2) | US8227450B2 (OSRAM) |
| EP (1) | EP1971615B1 (OSRAM) |
| JP (1) | JP2009517412A (OSRAM) |
| CN (1) | CN101405293B (OSRAM) |
| AU (1) | AU2006319716B2 (OSRAM) |
| CA (1) | CA2632095A1 (OSRAM) |
| ES (1) | ES2452718T3 (OSRAM) |
| WO (1) | WO2007062526A1 (OSRAM) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10149030A1 (de) | 2001-10-05 | 2003-04-10 | Viscum Ag | Stabile galenische gefriergetrocknete Arzneimittelzubereitung von rViscumin |
| US7388008B2 (en) | 2004-08-02 | 2008-06-17 | Ambrilia Biopharma Inc. | Lysine based compounds |
| JP2009517412A (ja) | 2005-11-30 | 2009-04-30 | アンブリリア バイオファーマ インコーポレイテッド | アスパルチルプロテアーゼ阻害物質のリジンベースのプロドラッグ及びその調製方法 |
| WO2008023273A2 (en) * | 2006-07-17 | 2008-02-28 | Ambrilia Biopharma Inc. | Method for improving pharmacokinetics |
| US8410300B2 (en) | 2006-09-21 | 2013-04-02 | Taimed Biologics, Inc. | Protease inhibitors |
| WO2009148600A2 (en) * | 2008-06-06 | 2009-12-10 | Concert Pharmaceuticals, Inc. | Deuterated lysine-based compounds |
| WO2010138338A1 (en) | 2009-05-27 | 2010-12-02 | Merck Sharp & Dohme Corp. | Hiv protease inhibitors |
| US9079834B2 (en) | 2010-10-28 | 2015-07-14 | Merck Canada Inc. | HIV protease inhibitors |
| US9133157B2 (en) | 2011-10-26 | 2015-09-15 | Merck Canada Inc. | HIV protease inhibitors |
| US10588980B2 (en) | 2014-06-23 | 2020-03-17 | Novartis Ag | Fatty acids and their use in conjugation to biomolecules |
| EP3463374A4 (en) * | 2016-05-31 | 2020-01-22 | Taimed Biologics, Inc. | A long acting pharmaceutical composition of protease inhibitor |
| US10369129B2 (en) | 2016-05-31 | 2019-08-06 | Taimed Biologics, Inc. | Long acting pharmaceutical composition of protease inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060025592A1 (en) * | 2004-08-02 | 2006-02-02 | Stranix Brent R | Lysine based compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5013861A (en) * | 1985-02-28 | 1991-05-07 | E. R. Squibb & Sons, Inc. | Ester substituted aminoalkanoylureido amino and imino acid and ester compounds |
| CA2089747A1 (en) | 1990-10-11 | 1992-04-12 | Gerd Schnorrenberg | Cyclopeptides, a method of preparing them, and their use as drugs |
| US5614522A (en) * | 1990-11-19 | 1997-03-25 | G.D. Searle & Co. | Retroviral protease inhibitors |
| EP0532466A3 (en) | 1991-09-12 | 1993-06-16 | Ciba-Geigy Ag | Derivatives of 5-amino-4-hydroxy-hexanoic acid and their therapeutical use |
| US6022994A (en) * | 1992-08-25 | 2000-02-08 | G. D. Searle &. Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| RU2146668C1 (ru) * | 1992-08-25 | 2000-03-20 | Джи Ди Сирл энд Компани | Сульфонилалканоиламино-гидроксиэтиламино-сульфонамидное соединение, фармацевтические композиции и способы лечения и ингибирования ретровирусных протеаз |
| KR100296461B1 (ko) * | 1992-08-25 | 2001-11-14 | 죤 에이치. 뷰센 | 레트로바이러스프로테아제저해제로서유용한n-(알카노일아미노-2-히드록시프로필)-술폰아미드 |
| JPH06321950A (ja) | 1993-05-14 | 1994-11-22 | Takeda Chem Ind Ltd | 水溶性ランカシジン誘導体 |
| BR9405573A (pt) | 1993-08-31 | 1999-09-08 | Teletotal Ltda | Método para faturar uma chamada telefônica |
| CA2183653A1 (en) | 1994-03-07 | 1995-09-14 | Roger Dennis Tung | Sulphonamide derivatives as aspartyl protease inhibitors |
| US5527829A (en) | 1994-05-23 | 1996-06-18 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
| JP4014220B2 (ja) * | 1995-01-20 | 2007-11-28 | ジー．ディー．サール アンド カンパニー | ビス−スルホンアミドヒドロキシエチルアミノ レトロ ウイルスプロテアーゼインヒビター |
| US5985870A (en) * | 1995-03-10 | 1999-11-16 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5776718A (en) * | 1995-03-24 | 1998-07-07 | Arris Pharmaceutical Corporation | Reversible protease inhibitors |
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| CA2243121A1 (en) | 1996-01-26 | 1997-07-31 | Francesco Gerald Salituro | Aspartyl protease inhibitors |
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| ID25551A (id) * | 1997-12-24 | 2000-10-12 | Vertex Pharma | Bahan baku obat penghambat protease aspartil |
| US6436989B1 (en) | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
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| WO2000077169A2 (en) * | 1999-06-16 | 2000-12-21 | Temple University - Of The Commonwealth System Of Higher Education | (z)-styryl acetoxyphenyl sulfides as cyclooxygenase inhibitors |
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| PL376900A1 (pl) | 2002-12-16 | 2006-01-09 | Boehringer Ingelheim International Gmbh | Zastosowanie kombinacji zawierającej nienukleozydowy inhibitor odwrotnej transkryptazy (NNRTI) i inhibitor cytochromu P450, taki jak inhibitor proteazy |
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| ES2319996T3 (es) | 2004-08-02 | 2009-05-18 | Ambrilia Biopharma Inc. | Compuestos basados en lisina. |
| ES2539527T3 (es) | 2005-04-27 | 2015-07-01 | Taimed Biologics, Inc. | Método para mejorar la farmacocinética de los inhibidores de las proteasas y de los precursores de los inhibidores de las proteasas |
| JP2009517412A (ja) * | 2005-11-30 | 2009-04-30 | アンブリリア バイオファーマ インコーポレイテッド | アスパルチルプロテアーゼ阻害物質のリジンベースのプロドラッグ及びその調製方法 |
| WO2008023273A2 (en) | 2006-07-17 | 2008-02-28 | Ambrilia Biopharma Inc. | Method for improving pharmacokinetics |
| US8410300B2 (en) * | 2006-09-21 | 2013-04-02 | Taimed Biologics, Inc. | Protease inhibitors |
-
2006
- 2006-11-30 JP JP2008542573A patent/JP2009517412A/ja active Pending
- 2006-11-30 CA CA002632095A patent/CA2632095A1/en not_active Abandoned
- 2006-11-30 EP EP06817683.3A patent/EP1971615B1/en active Active
- 2006-11-30 ES ES06817683.3T patent/ES2452718T3/es active Active
- 2006-11-30 AU AU2006319716A patent/AU2006319716B2/en not_active Ceased
- 2006-11-30 CN CN200680051907.4A patent/CN101405293B/zh not_active Expired - Fee Related
- 2006-11-30 WO PCT/CA2006/001963 patent/WO2007062526A1/en not_active Ceased
- 2006-11-30 US US12/086,184 patent/US8227450B2/en not_active Expired - Fee Related
-
2008
- 2008-06-19 US US12/214,995 patent/US8580995B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060025592A1 (en) * | 2004-08-02 | 2006-02-02 | Stranix Brent R | Lysine based compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101405293A (zh) | 2009-04-08 |
| AU2006319716A1 (en) | 2007-06-07 |
| EP1971615A1 (en) | 2008-09-24 |
| JP2009517412A (ja) | 2009-04-30 |
| ES2452718T3 (es) | 2014-04-02 |
| HK1124861A1 (en) | 2009-07-24 |
| US20090253926A1 (en) | 2009-10-08 |
| CA2632095A1 (en) | 2007-06-07 |
| EP1971615A4 (en) | 2011-06-22 |
| US8227450B2 (en) | 2012-07-24 |
| US20100130765A1 (en) | 2010-05-27 |
| US8580995B2 (en) | 2013-11-12 |
| WO2007062526A1 (en) | 2007-06-07 |
| EP1971615B1 (en) | 2014-01-01 |
| CN101405293B (zh) | 2013-03-13 |
| WO2007062526A8 (en) | 2007-08-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| PC | Assignment registered |
Owner name: TAIMED BIOLOGICS, INC. Free format text: FORMER OWNER WAS: AMBRILIA BIOPHARMA INC. |
|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |