EP0578745A1 - Composes contenant du phosphore et servant d'inhibiteurs de retrovirus - Google Patents
Composes contenant du phosphore et servant d'inhibiteurs de retrovirusInfo
- Publication number
- EP0578745A1 EP0578745A1 EP92910121A EP92910121A EP0578745A1 EP 0578745 A1 EP0578745 A1 EP 0578745A1 EP 92910121 A EP92910121 A EP 92910121A EP 92910121 A EP92910121 A EP 92910121A EP 0578745 A1 EP0578745 A1 EP 0578745A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- cyclohexyl
- isopropyl
- hydroxy
- ile
- Prior art date
- 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.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 119
- 241001430294 unidentified retrovirus Species 0.000 title abstract description 22
- 239000003112 inhibitor Substances 0.000 title description 11
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 4
- 229910052698 phosphorus Inorganic materials 0.000 title description 4
- 239000011574 phosphorus Substances 0.000 title description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 289
- -1 1-amino indanyl Chemical group 0.000 claims description 199
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 102
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 70
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
- 150000001412 amines Chemical class 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
- 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 20
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 claims description 13
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 10
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 8
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Chemical group 0.000 claims description 7
- 229910006069 SO3H Inorganic materials 0.000 claims description 6
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- HTYGJLSTEURLPB-VTOHDQHHSA-N (2r,3r,4r)-6-cyclohexyl-3,4-dihydroxy-n-[(2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]-5-[[(2s)-3-(1h-imidazol-5-yl)-2-[(2-naphthalen-1-yloxyacetyl)amino]propanoyl]amino]-2-propan-2-ylhexanamide Chemical compound O=C([C@H](CC=1NC=NC=1)NC(=O)COC=1C2=CC=CC=C2C=CC=1)NC([C@@H](O)[C@H](O)[C@@H](C(C)C)C(=O)NC1C2=CC=CC=C2C[C@H]1O)CC1CCCCC1 HTYGJLSTEURLPB-VTOHDQHHSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- UCOSRTUSVXHIMK-UHFFFAOYSA-N 1h-benzimidazol-2-ylmethanamine Chemical compound C1=CC=C2NC(CN)=NC2=C1 UCOSRTUSVXHIMK-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- UVEGMWQZKXTZMO-GEKCKTPHSA-N (2r,3r,4r)-6-cyclohexyl-3,4-dihydroxy-n-[(2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]-5-[[(2s)-3-hydroxy-2-[(2-naphthalen-1-yloxyacetyl)amino]butanoyl]amino]-2-propan-2-ylhexanamide Chemical compound O=C([C@@H](NC(=O)COC=1C2=CC=CC=C2C=CC=1)C(C)O)NC([C@@H](O)[C@H](O)[C@@H](C(C)C)C(=O)NC1C2=CC=CC=C2C[C@H]1O)CC1CCCCC1 UVEGMWQZKXTZMO-GEKCKTPHSA-N 0.000 claims description 3
- QIJRISQBRNSOTF-NKQLCSKJSA-N (2r,3r,4r)-6-cyclohexyl-3,4-dihydroxy-n-[(2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]-5-[[(2s)-3-hydroxy-2-[(2-naphthalen-1-yloxyacetyl)amino]propanoyl]amino]-2-propan-2-ylhexanamide Chemical compound O=C([C@H](CO)NC(=O)COC=1C2=CC=CC=C2C=CC=1)NC([C@@H](O)[C@H](O)[C@@H](C(C)C)C(=O)NC1C2=CC=CC=C2C[C@H]1O)CC1CCCCC1 QIJRISQBRNSOTF-NKQLCSKJSA-N 0.000 claims description 3
- RRZCDJAFNYSPLD-NYPWDDTMSA-N (2s,4s)-6-cyclohexyl-4-hydroxy-5-[[(2s)-3-hydroxy-2-[(2-naphthalen-1-yloxyacetyl)amino]butanoyl]amino]-n-[(3s)-3-methyl-1-oxo-1-(pyridin-2-ylmethylamino)pentan-2-yl]-2-propan-2-ylhexanamide Chemical compound O=C([C@@H](NC(=O)COC=1C2=CC=CC=C2C=CC=1)C(C)O)NC([C@@H](O)C[C@H](C(=O)NC([C@@H](C)CC)C(=O)NCC=1N=CC=CC=1)C(C)C)CC1CCCCC1 RRZCDJAFNYSPLD-NYPWDDTMSA-N 0.000 claims description 3
- FSDJNLCRSURYBE-JKTGEDSGSA-N (2s,4s)-6-cyclohexyl-4-hydroxy-5-[[(2s)-3-hydroxy-2-[(2-naphthalen-1-yloxyacetyl)amino]propanoyl]amino]-n-[(3s)-3-methyl-1-oxo-1-(pyridin-2-ylmethylamino)pentan-2-yl]-2-propan-2-ylhexanamide Chemical compound O=C([C@H](CO)NC(=O)COC=1C2=CC=CC=C2C=CC=1)NC([C@@H](O)C[C@H](C(=O)NC([C@@H](C)CC)C(=O)NCC=1N=CC=CC=1)C(C)C)CC1CCCCC1 FSDJNLCRSURYBE-JKTGEDSGSA-N 0.000 claims description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
- 150000001924 cycloalkanes Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims description 3
- LCGNACPGLVZVEB-IODDDSCESA-N (2S,4S,5S)-6-cyclohexyl-4-hydroxy-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-propan-2-yl-5-(3-pyridin-3-ylprop-2-enoylamino)hexanamide Chemical compound N1=CC(=CC=C1)C=CC(=O)N[C@H]([C@H](C[C@H](C(=O)N[C@@H]1[C@@H](CC2=CC=CC=C12)O)C(C)C)O)CC1CCCCC1 LCGNACPGLVZVEB-IODDDSCESA-N 0.000 claims description 2
- BLVQJUBWGQNMPI-AQGHBBIASA-N (2s,4s)-6-cyclohexyl-4-hydroxy-n-[(2s)-3-hydroxy-1-oxo-1-(pyridin-2-ylmethylamino)butan-2-yl]-5-[[(2s)-3-methyl-2-[(2-naphthalen-1-yloxyacetyl)amino]butanoyl]amino]-2-propan-2-ylhexanamide Chemical compound O=C([C@@H](NC(=O)COC=1C2=CC=CC=C2C=CC=1)C(C)C)NC([C@@H](O)C[C@@H](C(C)C)C(=O)N[C@@H](C(C)O)C(=O)NCC=1N=CC=CC=1)CC1CCCCC1 BLVQJUBWGQNMPI-AQGHBBIASA-N 0.000 claims description 2
- XBXDONBYTDPERN-KHUKWVIBSA-N (2s,4s)-6-cyclohexyl-4-hydroxy-n-[(2s)-3-hydroxy-1-oxo-1-(pyridin-2-ylmethylamino)propan-2-yl]-5-[[(2s)-3-methyl-2-[(2-naphthalen-1-yloxyacetyl)amino]butanoyl]amino]-2-propan-2-ylhexanamide Chemical compound O=C([C@@H](NC(=O)COC=1C2=CC=CC=C2C=CC=1)C(C)C)NC([C@@H](O)C[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)NCC=1N=CC=CC=1)CC1CCCCC1 XBXDONBYTDPERN-KHUKWVIBSA-N 0.000 claims description 2
- DAESEBURUKXLEX-MPIJBFAISA-N (2s,4s,5s)-6-cyclohexyl-4-hydroxy-n-[(2s)-3-hydroxy-1-oxo-1-(pyridin-2-ylmethylamino)butan-2-yl]-5-[[(2s)-3-(1h-imidazol-5-yl)-2-[(2-naphthalen-1-yloxyacetyl)amino]propanoyl]amino]-2-propan-2-ylhexanamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C(C)C)C(=O)N[C@@H](C(C)O)C(=O)NCC=1N=CC=CC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)COC=1C2=CC=CC=C2C=CC=1)C1CCCCC1 DAESEBURUKXLEX-MPIJBFAISA-N 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000006726 (C1-C5) alkenyl group Chemical group 0.000 claims description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- XNJDHMJJGQOQTR-RMDSEJHCSA-N N-[(2S,3S,5S)-1-cyclohexyl-3-hydroxy-6-methyl-5-[4-[(3-nitropyridin-2-yl)amino]but-2-enylcarbamoyl]heptan-2-yl]pyridine-2-carboxamide Chemical compound N1=C(C=CC=C1)C(=O)N[C@H]([C@H](C[C@H](C(=O)NCC=CCNC1=NC=CC=C1[N+](=O)[O-])C(C)C)O)CC1CCCCC1 XNJDHMJJGQOQTR-RMDSEJHCSA-N 0.000 claims description 2
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 2
- FYDKJFLLBYSHOS-KWWFGEDRSA-N [(1s,2r)-1-[[(2s,4s,5s)-6-cyclohexyl-4-hydroxy-2-propan-2-yl-5-(pyridine-2-carbonylamino)hexanoyl]amino]-2,3-dihydro-1h-inden-2-yl] acetate Chemical compound C([C@@H]([C@@H](O)C[C@@H](C(C)C)C(=O)N[C@H]1C2=CC=CC=C2C[C@H]1OC(C)=O)NC(=O)C=1N=CC=CC=1)C1CCCCC1 FYDKJFLLBYSHOS-KWWFGEDRSA-N 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- UNUPJRRJGKCOKU-MGZIXWBVSA-N n-[(2s,3s,5s)-1-cyclohexyl-3-hydroxy-5-[[(1s,2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]carbamoyl]-6-methylheptan-2-yl]pyridine-2-carboxamide Chemical compound C([C@@H]([C@@H](O)C[C@@H](C(C)C)C(=O)N[C@H]1C2=CC=CC=C2C[C@H]1O)NC(=O)C=1N=CC=CC=1)C1CCCCC1 UNUPJRRJGKCOKU-MGZIXWBVSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 20
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 7
- LOPKSXMQWBYUOI-UHFFFAOYSA-N 1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2C(N)C(O)CC2=C1 LOPKSXMQWBYUOI-UHFFFAOYSA-N 0.000 claims 2
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 51
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 26
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 13
- 150000005690 diesters Chemical class 0.000 abstract description 3
- 210000004962 mammalian cell Anatomy 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 347
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 314
- 239000000047 product Substances 0.000 description 147
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 116
- 238000002000 high resolution fast-atom bombardment mass spectrometry Methods 0.000 description 111
- 239000000243 solution Substances 0.000 description 105
- 238000002360 preparation method Methods 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 88
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
- 239000000741 silica gel Substances 0.000 description 77
- 229910002027 silica gel Inorganic materials 0.000 description 77
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 69
- 238000000034 method Methods 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 239000000203 mixture Substances 0.000 description 60
- 238000003756 stirring Methods 0.000 description 59
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 50
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 230000005764 inhibitory process Effects 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 238000003556 assay Methods 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 36
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 34
- 208000030507 AIDS Diseases 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000010265 fast atom bombardment Methods 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 239000000463 material Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 102000035195 Peptidases Human genes 0.000 description 24
- 108091005804 Peptidases Proteins 0.000 description 24
- 238000002143 fast-atom bombardment mass spectrum Methods 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 235000019198 oils Nutrition 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 241000725303 Human immunodeficiency virus Species 0.000 description 21
- 239000004365 Protease Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to compounds useful for inhibiting a retrovirus in a human cell infected with said retrovirus. More particularly, the present invention provides peptides, having at least one O-phosphate monoester or diester, and certain parent peptides thereof.
- AZT zidovudine
- HIV Human immunodeficiency virus
- infective and non-infective HIV-isolates Sequence analysis of the complete genomes from several infective and non-infective HIV-isolates has shed considerable light on the makeup of the virus and the types of molecules that are essential for its replication and maturation to an infective species (L. Ratner, et al., Nature, 313:277-284 (1985)). HIV exhibits the same gag/pol/env organization seen in other retroviruses (L.
- Reverse transcriptase is an enzyme unique to retroviruses that catalyzes the conversion of viral RNA into double stranded DNA. Blockage at any point during the transcription process, by AZT or any other aberrant deoxynucleoside triphosphate incapable of elongation, should have dramatic consequences relative to viral replication. Much work on the RT target is in progress based, in large measure, upon the fact that nucleosides like AZT are easily delivered to cells. However, the inefficiency of phosphorylation steps to the triphosphate, and the lack of specificity and consequent toxicity, constitute major drawbacks to use of AZT and similar nucleosides having a blocked, or missing, 3'hydroxyl group.
- the T4 cell receptor for HIV has also been targeted as an intervention point in AIDS therapy ( R.A. Fisher, et al., Nature, 331:76-78 (1988); R.E. Hussey, et al., Nature, 331:78-81 (1988); and K.C. Deen, et al., Nature, 331:82-84 (1988)).
- the exterior portion of this transmembrane protein, a molecule of 371 amino acids (sCD4) has been expressed in Chinese hamster ovary (CHO) cells and Genentech ( D.H. Smith, et al., Science, 238:1704-1707 (1987)) has had a product in clinical trials since the fall of 1987.
- CD4 based therapy the molecules can neutralize HIV by interfering with viral attachment to T4, and other cells which express CD4 on their surfaces.
- a variant on this theme is to attach cell toxins to CD4 for specific binding and delivery to infected cells which display glycoprotein gp-120 on their surfaces ( M.A. Till, et al., Science, 242:1166-1168 (1988); and V.K. Chaudhary, et al., Nature, 335:369-372 (1988)).
- HIV-fusion polypeptide precursors Another therapeutic target in AIDS involves inhibition of the viral protease (or proteinase) that is essential for processing HIV-fusion polypeptide precursors.
- the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome (Y.
- protease or proteinase
- the protease consisting of only 99 amino acids, is among the smallest enzymes known, and its demonstrated homology to aspartyl proteases such as pepsin and renin ( L.H. Pearl and W.R. Taylor, Nature, 329: 351-354 (1987); and I. Katoh, et al., Nature, 329:654-656 (1987)), led to inferences regarding the three-dimensional structure and mechanism of the enzyme (L.H. Pearl and W.R. Taylor, Nature, 329:351-354 (1987)) that have since been borne out experimentally. Active HIV protease has been expressed in bacteria (see, e.g., P.L. Darke, et al., J. Biol.
- TRH thyrotropin-releasing hormone
- WO 90/08550 discloses antivirals and methods for increasing the antiviral activity of AZT by administering AZT in combination with certain purine compounds or their prodrugs.
- Such prodrugs include 5-amino-3'-(2-methyl- 1-propoxycarbonyl)-1- ⁇ -D-ribofuranosyl-imidazole-4-carboxamide; 5-amino-3'-(1-propoxycarbonyl) 1- ⁇ -D-ribofuyranosyl-imidazole-4-carboxamide, and 2', 3'-cyclocarbonate AICA riboside.
- European published application 0 214 009 discloses enaminones as prodrugs of primary and secondary amines.
- U.S. Patent 4,650,803 discloses water soluble prodrugs of rapamycin such as the glycinate, propionate and pyrrolidine butyrate prodrugs.
- European published application 0 365 956 A2 discloses therapeutic compositions of amino-oxodihydroisoindolo-quinazoline which contain the radical of an amino acid, a dipeptide or a tripeptide which show enhanced solubility in water.
- U.S. Patent 4,163,058 and 4,260,769 disclose 5,5-diphenyl-hydantoins containing a phosphate group which offer enhanced solubility.
- Phosphorothioates are compounds in which one of the non-bridging oxygen atoms in the phosphate portion of the nucleotide is replaced by sulfur.
- Antimicrobial Patent Fast-Alert week ending 4 January 1991, discloses an in vitro hydrolyzable pro-drug combination of Methampicillin and the ⁇ -lactamace inhibitor Sulbactam which has therapeutic utility in the treatment of bacterial infections.
- European published application 0 354 108 discloses new O-sulphated or phosphorylated tyrosine analogues for treating central nervous system diseases.
- U.S. Patent 4,954,616 discloses the use of guanidine-related compounds, having a protecting group, such as triphenylphosphonoethyloxycarbonyl, in solution-phase peptide synthesis.
- Hyp is hydroxy-prolyl and wherein an example of a hydrophilic radical is phosphate.
- U.S. Patent 4,952,493 discloses a method for preparing selected peptide substrates for detecting the activity of virus-specified proteases.
- Specific tetrapeptide substrates are disclosed which are conjugates of protease-cleavable indicator groups and peptide sequences resembling picornavirus protease cleavage recognition sites.
- U.S. Patent 4,716,222 describes chromogenic substrates, such as 2H-7-O-(Phosphoryl)-4-methyl-8-nitrobenzopyran-2 -one, which are useful for the detection and determination of hydrolases, such as acid phosphatase.
- U.S. Patent 4,617,377 discloses new synergistine derivatives which may be substituted with a dialkylphosphoryloxy radical, which are useful as intermediates.
- phosphorus-containing haptens and immunogens comprising a phosphorus-containing hapten and a carrier molecule, which are useful for producing antibodies to catalyze the cleavage or formation of amide, ester or glycosidic bonds. It also discloses a method for treating acquired immune deficiency syndrome by inhibiting human immunodeficiency virus by treatment with a catalytic antibody elicited with a hapten or immunogen.
- Patent Fast- Alert week ending 22 February 1991, discloses phosphorylated glycosidase inhibitor prodrugs of desoxynojirimycin, which exhibit glycosidase inhibitory activity. They are useful in the treatment of gastrointestinal problems.
- psychotropic agents which may have a phosphatidylethanolamine chain at the C-terminus.
- European published application 0 338 372 discloses the N-phosphorylation of basic nitrogenous drug compounds to produce pro-drugs with enhanced water solubility or lipid solubility or reduced toxicity.
- the compounds of the present invention are O-phosphorylated. Furthermore, no where does this reference teach or suggest the peptidic compounds of the present invention.
- U.S. Patent 4,663,310 discloses renin inhibitors containing 2-substituted statine and which may have a phosphate-substituted phenyl group at the C-terminus.
- U.S. Patents 4,298,523 and 4,369,137 disclose solution phase methods, intermediates, and compositions for preparing useful peptides wherein a phosphate group is used as an amino- protecting group.
- U.S. Patent 4,661,473 discloses renin inhibitory peptides which may have a phosphate group at the C-terminus or in the peptide chain as part of a modified amino acid residue.
- U.S. Patent 4,661,472 discloses peptides which may be useful to treat steroid-dependent tumors.
- CLEOCIN PHOSPHATE ® Sterile Solution and CLEOCIN T ® Topical Gel, Topical Lotion and Topical Solution which are useful as antibiotics, contain clindamycin phosphate, which is a water soluble ester of clindamycin and phosphoric acid. It is biologically inactive and rapidly converted to active clindamycin. These drugs are currently manufactured and marketed by The Upjohn Company. See R.M. DeHaan, CM. Metzler. D. Schellenberg and W.D. Vandenboech, J. Clin. Pharmacol. 13, 190 (1973).
- phosphite-triester phosphorylation of protected serine-containing peptides
- European published applications 0 337 714 and 0 356 223 disclose HIV protease inhibitors which do not have an amino acid analog at the D-9 position in front of the transition state insert. These peptides may have phosphate-substituted aryl and Het groups in their transition state inserts, in the amino acid moieties occurring after their transition state inserts and at their C-terminus. They may also have phosphate-substituted alkyl and carbocyclic groups at their C-terminus. These applications also disclose peptides having a phosphate group in their peptide chain as part of a modified amino acid residue at their N-terminus and in their transition state inserts. However, no where do these applications disclose the phosphate groups of the present invention.
- European Patent Application 0 346 847 discloses amino acid derivatives having an optionally substituted trimethylene or tetramethylene groups or which carries a fused
- Non-phosphate peptides that are useful as renin inhibitors: European published application 0 173 481 and U.S. Patent 4,880,781; U.S. Patent 4,864,017 (having diol transition state inserts); European published application 0 364 493, published 25 April 1990, (having aryl acid derived moieties at the N-terminus); and European published application 0 397 779, published 22 November 1990, (having N-terminal polar end groups).
- PCT International Publication Number WO 91/06561 published 16 May 1991, discloses a method for treating HIV and other retroviruses and non-phosphate peptides useful therefor.
- the present invention particularly provides:
- C 8 is absent or a divalent moiety of the formula XL 1 , XL 2 , XL 2a , XL 2b or other amino acyl derivative;
- D 9 is Pro, absent or a divalent moiety of the formula XL 3 , XL 2a , XL 2b or other amino acyl derivative;
- E 10 -F 11 is a divalent moiety of the formula XL 6 , XL 6b , XL 6c , XL 6d , XL 6e , II, III, IV, XL 6p , XL 6cp , XL 6ep , XL 6ccp , II cp , V, Vp, VI or VII;
- G 12 is absent or a divalent moiety of the formula XL 4 , XL 4a or other amino acyl derivative
- R 4 at each occurrence is the same or different as is a) hydrogen
- R 1 1 is -R or -R 2 ;
- R 12 is -(CH 2 ) n -R 13 ;
- R 25 is a) -(CH 2 ) n -R 13 ,
- R 30 and R 31 together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one -CH 2 -group is replaced by -NH-, -N(alkoxycarbonyl)-, -N(acyl)- or -S- or which carries a fused cycloalkane, aromatic or heteroaromatic ring;
- j is zero or one
- n is one to three, inclusive
- n is independently an integer of zero to six, inclusive; wherein p is zero to two, inclusive;
- q is an integer of one to six, inclusive
- r is zero to five, inclusive
- s is an integer of zero or one so that the sum of u plus v plus s is three or four;
- t is an integer of zero to three, inclusive
- u is an integer of zero to three, inclusive
- v is an integer of zero to four, inclusive
- w is an integer of two or three;
- x is an integer of two to seven, inclusive
- y is an integer of zero to six, inclusive.
- z is an integer of zero to six so that the sum of y plus z does not exceed six; wherein aryl is phenyl or naphthyl substituted by zero to three of the following: a) C 1 -C 3 alkyl,
- -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and substituted by zero to three of the following:
- amino acyl derivatives any of the naturally occurring amino acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof. These compounds may be in the L or D configuration and are well known and readily available to those skilled in the art. It also includes the phosphate ester of serine, threonine, and tyrosine.
- phosphate monoesters include the phosphate esters of alkanols and hydroxy-substituted aromatic and heterocyclic moieties.
- Phosphate diesters include the cyclic phosphate esters derived from dihydroxy alkanes in which the hydroxyl groups are on adjacent carbons (1,2-diols) or on carbons separated by one carbon atom (1,3-diols).
- the present invention provides for the O-phosphorylation of compounds to produce pro-drugs with enhanced water solubility, bioavailability, improved absorption, increased duration of action, or reduced toxicity.
- the pro-drugs are hydrolyzed in the body, regenerating the original (parent) drugs with the release of a salt of phosphoric acid.
- the parent compounds of the compounds of the present invention are effective and potent inhibitors of HIV protease. They have also been found to inhibit HIV protease in cell cultures, as described below. Therefore, the parent compounds of the compounds of formula I inhibit retroviral proteinases and thus inhibit the replication of the virus. They are useful for treating patients infected with human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
- HIV human immunodeficiency virus
- AIDS acquired immunodeficiency syndrome
- the parent compounds have low to moderate renin inhibitory activity but are surprisingly and unexpectedly potent retroviral protease inhibitors.
- both the parent compounds and the pro-drug compounds of the present invention are useful as retroviral protease inhibitors.
- parent compounds of the present invention include:
- X 1 is X 2 -[(CH 2 ) 2 -O] m -aryl-O-(CH 2 ) n -C(O)-;
- m is five or six
- n is zero to six, inclusive
- D 9 is the moiety XL 3 ;
- E 10 -Fu is the moiety XL 6 or II;
- G 12 is absent or is the moiety XL 4 ;
- aryl is phenyl or naphthyl
- -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen;
- the peptides of the present invention are useful as novel human retroviral protease inhibitory peptide analogs. Therefore, the peptides inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
- a human retrovirus such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
- the capsid and replicative enzymes (i.e. protease, reverse transcriptase, integrase) of retroviruses are translated from the viral gag and pol genes as polyproteins that are further processed by the viral protease (PR) to the mature proteins found in the viral capsid and necessary for viral functions and replication. If the PR is absent or nonfunctional, the virus cannot replicate.
- the retroviral PR such as HIV-1 PR, has been found to be an aspartic protease with active site characteristics similar to those exhibited by the more complex aspartic protease, renin.
- human retrovirus includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, as well as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) or strains apparent to one skilled in the art, which belong to the same or related viral families and which create similar physiological effects in humans as various human retroviruses.
- Patients to be treated would be those individuals: 1) infected with one or more strains of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) in the case of HIV, having either an asymptomatic HIV infection or a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis including pneumocystic pneumonia iv) non-Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4+ lymphocyte count of less than 500/mm 3 in the peripheral blood.
- Treatment would consist of maintaining an inhibitory level of the peptide used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
- an example of one such human retrovirus is the human
- HIV immunodeficiency virus
- HTLV-III or LAV human acquired immunodeficiency syndrome
- AIDS human acquired immunodeficiency syndrome
- HIV-I protease a retro viral encoded protease
- cleaves the fusion polypeptides into the functional proteins of the mature viral particle E.P. Lillehoj, et al., J. Virology, 62:3053 (1988); C. Debuck, et al., Proc. Natl. Acad. Sci., 84:8903 (1987).
- HIV-I protease This enzyme, HIV-I protease, has been classified as an aspartyl protease and has a demonstrated homology to other aspartyl proteases such as renin, L.H. Pearl, et al., Nature 329:351 (1987); I. Katoh, et al., Nature 329:654 (1987). Inhibition of HIV-I protease blocks the replication of HIV and thus is useful in the treatment of human AIDS, E.D. Clerq, J. Med. Chem. 29:1561 (1986). Inhibitors of HIV-I protease are useful in the treatment of AIDS.
- Pepstatin A a general inhibitor of aspartyl proteases, has been disclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al, Proc. Natl. Acad. Sci. USA, 85:6612 (1986).
- Other substrate derived inhibitors containing reduced bond isosteres or statine at the scissle position have also been disclosed, M.L. Moore, et al., Biochem. Biophys, Res. Commun. 159:420 (1989); S. Billich, et al., J. Biol. Chem. 263:17905 (1988); Sandoz, D.E. 3812-576-A.
- the peptides of the present invention are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS).
- AIDS human acquired immunodeficiency disease syndrome
- the peptides are also useful for treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus.
- viruses that infect cats include, for example, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia. Exact dosages, forms and modes of administration of the peptides of the present invention to non-human animals would be apparent to one of ordinary skill in the art, such as a veterinarian.
- parent compounds and the phosphate prodrug compounds of formula I of the present invention are prepared as described in the Preparations and Examples below, or are prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in the art of peptide synthesis.
- Chart A describes the preparation of the cyclic phosphate 1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-O,O-hydroxyphosphoryl-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide (Formula A-3).
- Chart B describes the preparation of the phosphate peptide 1-Naphthoxyacetyl-L- histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-O-phosphate-L-seryl-2-pyridylmethylamide (Formula B-10).
- Boc-serine (B-1) with 2-pyridylmethylamine (B-2) with BOP reagent gives the adduct B-3.
- the tert-butyloxycarbonyl group is removed with trifluoroacetic acid and the resulting amine isolated as the bis trifluoroacetate salt (B-4).
- This amine is coupled to the known acid 5S-tert-butyloxycarbonylamino-4S-tert-butyldimethylsilyloxy-6-cyclohexyl-2S- isopropyl-hexanoic acid using BOP reagent to give compound B-5.
- Chart C describes the preparation of the parent peptide Cyclohexanecarbonyl-4S-amino-6-cyclohexyl-3R, 4R-dihydroxy-2R-isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide.
- Chart D describes the preparation of the parent peptide N-(4-Quinolinyl)oxyacetyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide (Formula D-5).
- 4-Hydroxyquinoline D-1 is alkylated with tm-butyl-bromoacetate using potassium hydride to give compound D-2.
- the tert-butyl ester protecting group is removed with trifluoroacetic acid to give the free acid D-3.
- Chart E describes the preparation of the parent peptides 3R-Quinuclidineaminocarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethyl-amide (Formula E-3) and 3S-Quinuclidineaminocarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide (Formula E-4).
- 3-Aminoquinuclidine dihydrochloride is neutralized with sodium hydroxide to give the free base E-1.
- This amine E-1 is treated with p-nitrophenylchloroformate and the resulting material reacted with 5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide E-2 and diisopropylethylamine to give the two isomeric peptides E-3 and E-4.
- Chart M describes the preparation of a biotinol C-terminus segment for coupling to the transition state insert. This segment is used in the preparation of 2-((4-([3aS-(3a ⁇ ,4 ⁇ ,6a ⁇ )]-1H-thieno[3,4-d]imidazol-2(3H)-on-4yl)pent-1-yl)oxy)benzoyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2Risopropyl-hexanoyl-L-isoleucinyl-2-aminomethylpyridine.
- the compound M-l which is commercially available or prepared by procedures described in K. N. Parameswaran, Org. Prep. Proc. Intl. 1990, 22, 119-121, is converted to the compound M-2, by using NaB ⁇ 4 /T ⁇ F/ ⁇ MPA.
- the compound M-2 is reacted with Mesyl Cl, pyridine to obtain the compound M-3.
- the compound M-3 is reacted with the compound M-4, which is commercially available, in the presence of K 2 CO 3 /DMF to obtain the compound M-5.
- the compound M-5 is reacted with NaOH/MeOH to achieve the C-terminal segment M-6.
- the N-terminal segment used in the preparation of 2-((4-([3aS-(3a ⁇ ,4 ⁇ ,6a ⁇ )]-1H-thieno[3,4-d]imidazol-2(3H)-on-4yl)pent-1-yl)thio)benzoyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2Risopropyl-hexanoyl-L-isoleucinylamino-2-(4-methylthiazol-5yl)ethane, is prepared.
- Chart N describes the preparation of the methylthiazole C-termini for coupling to the transition-state insert segment.
- the segment N-4 is used in the preparation of 2-(2-(4- methylthiazol-5-yl)ethyl)oxy)benzoyl-5S-amino-6-cyclohexyI3R,4R-dihydroxy-2R-isopropylhexanoyl-L-isoleucinyl-2aminomelhylpyridine and 2-(2-(4-methylthiazol-5-yl)ethyl)oxy)benzoyl- 5S-amino-6-cyclohexyl3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucinyl-1- aminoethyl(4methylthiazole).
- the segment N-9 is used in the preparation of 2-(2-(4- methylmiazol-5-yl)ethyl)thio)benzoyl-5S-amino-6cyclohexyl-3R,4R-dihydroxy-2R-isopropylhexanoyl-L-isoleucinyl-2aminomethylpyridine and 2-(2-(4-methylthiazol-5-yl)ethyl)thio)benzoyl- 5S-amino-6cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucinyl laminoethyl(4- methylthiazole).
- the compound N-3 is reacted with NaOH/MeOH to achieve the compound N-4.
- the compound N-5 which is commercially available, is reacted with PBr 3 /pyridine to obtain the compound N-6.
- the compound N-6 is reacted with the compound N-7, in the presence of K 2 CO 3 /DMF to obtain the compound N-8.
- the compound N-8 is converted to the compound N-9 by using NaOH/MeOH.
- Chart O describes the preparation of the (3R,4R)-Leu ⁇ [CH(OH)CH(OH)] Dehydroleu insert by a diastereoselective aldol (D.A. Evans, et al., Tetrahedron Lett. 1986, 27, 4957- 4960), C-terminus functionalization and protecting group removal.
- the compounds of the present invention can occur in several diastereomeric forms, depending on the configuration around the asymmetric carbon atoms. All such diastereomeric forms are included within the scope of the present invention.
- the stereochemistry of the amino acids corresponds to that of the naturally occurring amino acids.
- the present invention provides for compounds of formula I or pharmacologically acceptable salts and/or hydrates thereof.
- Pharmacologically acceptable salts refers to those salts which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailablility.
- the compounds of the present invention are useful for treating patients infected with human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
- HIV human immunodeficiency virus
- AIDS acquired immunodeficiency syndrome
- they are administered by oral, nasal, transdermal and parenteral (including i.m. and i.v.) routes in doses of 1 mg to 100 mg/kg of body weight.
- the compounds of this invention into appropriate pharmaceutical dosage forms.
- the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
- Solid compositions are prepared by mixing the compounds of this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers.
- Capsules are prepared by mixing the compounds of this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
- Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds of this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
- Syrups are prepared by dissolving the compounds of this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
- Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
- Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
- parenteral solutions are prepared by dissolving the compounds of this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule.
- Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds of this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
- Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either an asymptomatic HIV infection or a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia, iv) non-Hodgkin's lymphoma, or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4+ lymphocyte count of less than 500/mm 3 in the peripheral blood.
- Treatment would consist of mamtaining an inhibitory level of the compounds of this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
- the HIV-1 protease has been expressed in E. coli, isolated, characterized and used to determine the inhibitory constants (K I ) of potential inhibitory compounds as follows:
- the synthetic peptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-OH serves as the substrate for the measurement of HIV-1 protease activity.
- This peptide corresponds to the sequence from residue 128 to 135 in the HIV gag protein. Cleavage of the synthetic peptide, as well as the gag protein, takes place at the Tyr-Pro bond. HIV-1 protease activity is measured at 30 °C in 50 mM sodium acetate, pH 5.5, containing 10% glycerol, 5% ethylene glycol, 0.1% Nonidet P-40 and 2.8 mM substrate in a total volume of 50 ⁇ .
- CV-1 cells were seeded at 2 x 10 "5 cells/well in 24 well Costar dishes and infected 6 to
- test compounds were dissolved in DMSO containing 2.5% fetal bovine serum and added to triplicate wells immediately after virus addition.
- the culture medium was removed, the monolayer washed with 1 ml of PBS and the cells lysed by the addition of 0.1 ml of loading buffer (62.5 mM Tris-H Cl pH 6.8, 2.3% SDS, 5% B-mercaptoethanol, 10% glycerol).
- the cells lysates were collected individually, placed in boiling water for 3 minutes, and then 0.025 ml of each is subjected to electrophoresis on 12% SDS-polyacrylamide gels.
- the proteins were electroblotted onto nitrocellulose and analyzed by Western blotting.
- the primary antibodies were sheep anti-Pr24 and sheep anti-Pr17 and the secondary antibody in both cases was alkaline-phosphatase conjugated rabbit-anti sheep IgG (all obtained from Kirkegaard & Perry Laboratories, Gaithersburg, MD).
- Test compounds significantly inhibited proteolysis of the HIV-1 gag polyprotein (Pr55) to the mature viral structural proteins Pr24 and Prl7 in the above cells infected with the recombinant vaccina virus expressing the HIV-1 gag-pol genes.
- the HIV-1 like particles released from inhibitor-treated cells contained almost exclusively Pr55 and other gag precursors, but not Pr24.
- the preferred parent compounds of the prodrug compounds of the present invention are:
- Aai is 1S-amino-2R acetoxy-indane
- Ahi is 1S-amino-2R-hydroxy-indane
- Amb is 2-aminomethylbenzimidazole
- Amp is 2-(aminomethyl) pyridine
- Amp-NO is (2-pyridylmethyl) amino (pyridine N-oxide);
- Apb is 4-[(3-amino-2-pyridinyl)amino]-2-butenyl-amine
- Biotinoyl is 4-([3aS-(3a ⁇ ,4 ⁇ ,6a ⁇ )]-1H-thieno[3,4-d]imidazolyl)-pentanoyl-; Boc is t-butoxycarbonyl;
- BOC-ON is 2-(tert-butoxycarbonyl-oxyimino)-2-phenylacetonitrile
- BOP is benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
- BroP is Bromo tris (dimethylamino) phosphonium hexafluorophosphate
- Bz or Bzl is benzyl
- Cbz is benzyloxycarbonyl
- CcD is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 4 , is ⁇ - hydroxy and R 3 is ⁇ -CH 2 -cyclohexyl;
- CCD is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 3 is ⁇ - CH 2 -cyclohexyl and R 4 , is ⁇ -hydroxy;
- CDCl 3 is deuteriochloroform
- Celite is a filter aid
- CVA is Cha ⁇ [CH(OH)CH 2 ]Val of formula X wherein R 1 , is cyclohexyl, R 2 , is hydrogen, R 3 is ⁇ -isopropyl and R 4 , is ⁇ -hydroxy and is preferably 5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl-hexanoyl;
- chpVA is the moiety of formula X wherein R 1 , is cycloheptyl, R 2 , is hydrogen, R 3 is ⁇ -isopropyl, and R 4 , is ⁇ -hydroxy;
- CLA is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is hydrogen, R 3 is - ⁇ -isobutyl, and R 4 , is ⁇ -hydroxy;
- CLD is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 4 , is ⁇ -hydroxy and R 3 is ⁇ -isobutyl;
- CPD is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 4 , is ⁇ -hydroxy and R 3 is ⁇ -benzyl;
- CVD is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 3 is ⁇ -isopropyl and R 4 , is ⁇ -hydroxy and is preferably 5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl;
- CVD' is the moiety of formula X wherein R 1 , is cyclohexyl, R 2 , is ⁇ -hydroxy, R 4 , is ⁇ -hydroxy, and R 3 is ⁇ -isopropyl;
- CVP or (OPO 3 H 2 )CVA is 5S-amino-6-cyclohexyl-4S-(O-phosphoryl)-2S-isopropyl-hexanoyl;
- DANS is dansyl or 5-dimethylaminonaphthalenesulfonyl
- Dat is des-amino-tyrosine
- DCC is dicyclohexylcarbodiimide
- DEPC diethylphosphoryl cyanide
- Des-amino-tyrosine means the hydrogen atom of the hydroxy group of the des-amino tyrosine amino acid is substituted by -OPO 3 H 2 ;
- DIPEA is N,N-diisopropylethylamine
- DMF is N,N-dimethylformamide
- DMSO dimethylsulfoxide
- DNP is 2,4-dinitrophenyl
- ET 3 N is triethylamine
- ET 2 O is diethylether
- EtOAc is ethyl acetate
- FAB fast atom bombardment
- g is grams
- Glu is glutamine
- ⁇ -Glu is ⁇ -glutamyl acid
- Gly is glycine
- Gin is glutamine
- Hexaeg is hexa(ethyleneglycol);
- Hmb is 2-hydroxy-3-methyl-butyryl
- Hyb is 2-hydroxybenzoyl
- N-MeHis is N ⁇ -methyl histidine
- HOBT is 1-hydroxybenzotriazole
- HOAc is acetic acid
- Hpa is 2-hydroxyphenethylamine at the C-terminus or is hydroxyphenylacetyl at the N- terminus;
- HPLC high performance liquid chromatography
- Hsr is L-homoserine
- Ile is L-isoleucine
- IR is infrared spectrum
- Iva is isovaleryl
- LCA is the moiety of formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is - ⁇ -CH 2 -cyclohexyl and R 4 is ⁇ -hydroxy;
- LFA is the difluoro ketone version of statine analogue as described more fully in PCT Pub. No. WO86/06379 (6 November 1985), and is the moiety of formula IV wherein R 1 is cyclohexylmethyl;
- LFD is -L-Leu-[R,R-CH(OH)CH(OH)Phe- or 5S-amino-2S-benzyl-3R,4R-dihydroxy-7 methyl-octanoyl;
- LLA is the moiety of formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is - ⁇ - isobutyl, and R 4 is ⁇ -hydroxy;
- LID is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ - hydroxy and R 3 is ⁇ -isobutyl;
- LLd is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ - hydroxy, and R 3 is ⁇ -isobutyl;
- LLD is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ - hydroxy, and R 3 is ⁇ -isobutyl;
- LPA is the moiety of formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is - ⁇ - benzyl and R 4 is ⁇ -hydroxy;
- LVA is Leu ⁇ (CH(OH)CH 2 )VaI with the S configuration at C4 (the hydroxyl-bearing carbon atom) of the formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is ⁇ -isopropyl and R 4 is ⁇ -hydroxy;
- LVD is the diol version of LVA as described more fully in PCT Pub. No.
- LVDA' is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy, and R 3 is ⁇ -isopropyl;
- Mba is 2S-methylbutylamine
- Me is methyl
- Meb is 2-[(2-methoxy)ethoxy]benzoyl
- Mee is 2-[2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]benzoyl
- MeOH is methanol
- Mep is 3-[2-(2-methoxy)ethoxy)ethoxy]pyridyl-2-carbonyl;
- ml is milliliter
- Moc is methoxycarbonyl
- Morph is 4-morpholinecarbonyl
- Mpb is 4-methyI-2-[(2-phenoxy)ethoxy]benzoyl
- Mpc is 3-[2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]pyridyl-2-carbonyl;
- MPLC medium pressure liquid chromatography
- MS is mass spectroscopy
- Mtb is 2-[2-(2-methoxy)ethoxy)ethoxy]benzoyl
- Npb is 4-[(3-nitro-2-pyridinyl)amino]-2-butenylamine
- Npe is 2-[(3-nitro-2-pyridinyl)amino]ethylamine
- NOA is (1-naphthyloxy)acetyl
- O-phosphoryl is -OPO 3 H 2
- OPO 3 K 2 -Ser means the hydrogen atom of the hydroxy group of the serine amino acid is substituted by -OPO 3 K 2 ;
- OPO 3 K 2 -Thr means the hydrogen atom of the hydroxy group of the threonine amino acid is substituted by -OPO 3 K 2 ;
- Peb is 2-[(2-phenoxy)ethoxy]benzoyl
- Pentaeg is penta(ethyleneglycol);
- Pep is 3-[(2-phenoxy)ethoxy]propionyl or is 2-[(2-phenoxy)ethoxy]benzoyl;
- Ph is phenyl
- Phe is phenylalanine
- POA is phenyloxyacetyl
- Ppc is 3-[2-(phenoxy)ethoxy]pyridyl-2-carbonyl
- PPD is the moiety of formula X wherein R 1 is phenyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -benzyl;
- Pro is L-proline
- Ptb is 2-[(phenylthio)methoxy]benzoyl
- Ptc is 3-[(phenylthio)methoxy]pyridyl-2-carbonyl
- 2-Py-Ala is D,L-(3-pyridyl)-alanine
- Ser is L-serine
- TBA or Tba is t-butylacetyl
- TBDMS is tert-butyldimethylsilyl
- TBAP is tetra-n-butylammonium phosphate
- TEA is triethylamine
- TFA is trifluoroacetic acid
- THF is tetrahydrofuran
- Thr is L-threonine
- TLC is thin layer chromatography
- Tma is tert-butylmethylamine
- Tos is p-toluenesulfonyl
- Trieg is tri(ethyleneglycol);
- TsOH is p-toluenesulfonic acid
- Tyr is tyrosine
- (OCH 3 )Tyr is O-methyl tyrosine
- Val is L-valine.
- the wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon.
- the dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon.
- L-Isoleucinamide N-(5-amino-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp;
- L-Histidinamide N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)-amino]carbonyl]butyl]amino]-5-oxopentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc-Phe-His-LCA-Ile-Amp;
- L-Histidinamide N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-(2,3-dihydroxy-5-methyl-1-(2-methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl)-amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2S*,3R*,4-Amp; or Boc-Phe-His-LVDA'-Ile-Amp; FAB-MS: [m + H] + at 835.5084;
- Silica gel used for chromatography is obtained from E. Merch A.G., Darmstadt, Germany.
- Silica gel GF, 250 micron slides obtained from Analtech, Inc., Newark, DE are used for TLC.
- Celite is a filter aid manufactured by Johns-Manville, New York.
- FAB mass spectra are obtained on a Varian CH5 mass spectrometer, IR spectra on a Digilab FTS15E and NMR spectra on a Brucker AM300. Melting points are taken in capillary tubes and are uncorrected.
- a 5% solution of the Boc protected amine in an equal volume of methylene chloride and trifluoracetic acid is allowed to stir at room temp (temperature) for 1-3h and then concentrated in vacuo.
- a solution of the residue in methylene chloride is washed once with aqueous sodium bicarbonate. The aqueous wash is backwashed twice with methylene chloride. The combined organic fractions are dried over magnesium sulfate and concentrated in vacuo. The residue is then used as is in the next step without further purification.
- Procedure B Coupling an acid to an amine using diethyl cyanophosphonate (DEPC): To a nitrogen covered 0.04 molar solution of the free amine in methylene chloride is added 1.25 equivalents of the acid followed by 1.25 equivalents of triethylamine and 1.4 equivalents of diethyl cyanophosphonate (DEPC). The solution is allowed to stir at room temperature for 2-24 hr, diluted with methylene chloride, and washed once with aqueous sodium bicarbonate. The aqueous fraction is backwashed twice with methylene chloride. The organic fractions are combined, dried over magnesium sulfate, and concentrated in vacuo. The residue is then chromatographed over silica gel to yield the coupled product.
- DEPC diethyl cyanophosphonate
- Procedure C Coupling an amine to an acid using diethyl cyanophosphonate (DEPC): To a nitrogen covered 0.04 molar solution of the acid in methylene chloride is added
- e(%) is the maximum percent of solvent B for the gradient phase of the preparative separation
- t o is the retention time (min) for unretained materials on the analytical column
- t is the longest retention time (min) for the products of interest.
- the analytical separation is usually carried out with an isocratic elution phase followed by a linear gradient from the isocratic solvent concentration to 100% solvent B.
- x represents the duration (min) of the isocratic portion of the separation and y represents the duration (min) of the gradient portion.
- a (%) and B(%) represent the percent of solvents A and B in the initial isocratic solvent mixture.
- Part B in 1.2 ml of methylene chloride is added dropwise 1.2 ml of trifluoroacetic acid.
- the ice bath is removed and after stirring at room temperature for 3 hr, the solution is concentrated in vacuo.
- a solution of the residue in methylene chloride is washed once with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo.
- the residue is chromatographed over silica gel (3.5% methanol: 0.35% ammonium hydroxide: methylene chloride) to yield 0.0802 g of the titled product.
- CV-1 Assay 100% at 10 ⁇ M; 82% 1 ⁇ M; 18% at 0.3 ⁇ M; 1 % at 0.1 ⁇ M.
- Elution is carried out first using 3% methanol: methylene chloride containing 0.3% ammonium hydroxide collecting 12 ml fractions. At fraction 137, the solvent is changed to 5% methanol:methylene chloride containing 0.5% ammonium hydroxide and then at fraction 277 the solvent is changed to 30% methanol :methylene chloride containing 0.5% ammonium hydroxide and 21 ml fractions are then collected. Fractions 366-420 are combined to yield 1.52 g of the titled product.
- the structure is supported by NMR, IR, and mass spectra.
- Preparation 108 is allowed to react first with di-tert-butyl N,N-diethylphorphoramidite and 1H-tetrazole and then with m-chloroperoxybenzoic acid to give N ⁇ -[(2S,4S,5S)-5-[N-(2-pyridinylcarbonyl)amino]-6-cyclohexyl-4-(O-di-tert-butylphosphoryl)-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyI]-L-isoleucinamide which is treated with concentrated hydrochloride acid to give the titled product.
- PREPARATION 110 N ⁇ -[(2S,4S,5S)-5-(tert-Butoxy carbonylamino)-4-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2-isopropyl-1-oxohexyl]-N-(2-pyridinyl)methyl]- L-isoleucinamide or Boc (OTBDMS) CVA Ile Amp.
- the structure is supported by NMR.
- PREPARATION 112 N ⁇ -[(2S,4S,5S)-5-[N-(2-Pyridinylcarbonyl)amino]-6-cyclohexyl-4- hydroxy-2-isopropyl-1-oxohexyI]-N-(2-pyridinylmethyl)-L-isoleucinamide or 2-Pyridinylcarbonyl-CVA-Ile-Amp.
- the structure is supported by NMR.
- CV-1 Assay (% Inhibition): 85% at 10 ⁇ M; 84% at 10 ⁇ M; 65% at 3 ⁇ M; 40% at 1 ⁇ M; 16% at 0.3 ⁇ M; 11 % at 0.1 ⁇ M.
- HIV-1 Protease K I , nM: 30.
- CV-1 Assay (% Inhibition): 57% at 1 ⁇ M; 68% at 1 ⁇ M.
- the structure is supported by NMR.
- PREPARATION 114 N ⁇ -[(2S,4S,5S)-5-[N-[2-(3-Pyridinyl)ethylcarbonyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or 3-Pyridinyl-(CH 2 ) 2 -C(O)-CVA-Ile-Amp.
- CV-1 Assay (% Inhibition): 18% at 1 ⁇ M; 50% at 1 ⁇ M.
- the product from Preparation 114 is allowed to react first with di-tert-butyl N,N-diethylphosphoramidite and 1H-tetrazole and men with m-chloroperoxybenzoic acid to give N ⁇ -[(2S,4S,5S)-5-[N-[2-(3-pyridinyl)-ethylcarbonyl]amino]-6-cyclohexyl-4-(0-di-tert-butylphosphoryl)-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide which is treated with concentrated hydrochloric acid to give the titled product.
- a nitrogen covered mixture of 5.0 g of 4-chloro-2, 6-diaminopyrimidine in 60 ml of ethylenediamine is heated at 85° for 24 hr at 130° for 22 hr and then allowed to stand at room temperature for 24 h.
- the residual ethylenediamine is removed by distillation and the pot residue is slurried in 1:1 methanol :methylene chloride.
- the suspended solid (4.855 g) is collected on a filter and dried under vacuum. A portion (0.5 g) of this solid residue is chromatographed over a 50 ml silica gel column (elution with 50% methanol:methylene chloride containing 1% ammonium hydroxide) and 4.8 ml fractions are collected. Fractions 47-110 are combined to yield 0.323 g of the title product.
- the structure is supported by mass spectrum, found M + at m/z 168.
- a mixture of flame-dried lithium chloride (0.020 g) and the product from Preparation 116 (0.100 g) in tetrahydrofuran (5 ml) is stirred, under nitrogen at ambient temperature for 18 hr; the solids have dissolved to give a gel.
- This mixture is then treated with 1H-tetrazol (0.053 g) and di-tert-butyl N,N-diethylphosphoramidite (0.11 ml) and stirred at ambient temperature for 24 hr. Additional 1H-tetrazol (0.053 g) and di-tert-butyl N,N-diethylphosphoramidite (0.11 ml) are added and stirring is continued for 24 hr.
- tetrahydrofuran (0.2 ml), under nitrogen, is treated with concentrated hydrochloric acid (0.1 ml), kept at ambient temperature for 1.3 hr. and concentrated under a stream of nitrogen to one third of its original volume. The residue is treated with water (3 ml) and freeze dried to give a waxy solid. A portion of this material is chromatographed on a preparative HPLC column (see general Procedure E). Elution is isocratic at 83% solvent A: 17% solvent B for 15 min.
- EXAMPLE 6 1 -Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-O,O-phosphoryl- 2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide (Formula A-3) Refer to Chart A.
- lithium chloride 8 mg is flame-dried under reduced pressure and allowed to cool to room temperature under argon.
- CV-1 Assay (% Inhibition): 86% at 10 ⁇ M; 24% at 1 ⁇ M.
- PREPARATION 120 1-Naphthoxyacetyl-N im -tert-butyloxycarbonyl-L-histidyl-5S-amino-4S- tert-butyldimethylsilyloxy-6-cyclohexyl-2S-isopropyl-hexanoyl-L-seryl-2- pyridylmethylamide (Formula B-8) Refer to Chart B.
- PREPARATION 122 3-[3(R)-[3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-(2-methylcyclohexyl)-5(R)-oxazolidinyl]-3-hydroxy-2(R)-isobutyl-1-oxopropyl]- 4(R)-methyl-5(S)-phenyl-2-oxazolidinone (Formula C-3) Refer to Chart C.
- the reaction is stirred for an additional hour, warmed to room temperature and partioned between dilute phosphate buffer and dichloromethane.
- the aqueous layer is extracted with additional portions of dichloromethane and the resulting organic layers are combined, dried (magnesium sulfate), and concentrated under reduced pressure.
- the residue is flash chromatographed (15% to 30% ethyl acetate in hexanes) on silica gel to afford 0.81 g of the titled product as a white foam.
- PREPARATION 124 3-[3(R)-[3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-(2-methylcyclohexyl)-5(R)-oxazolidinyl]-3-hydroxy-2(R)-isobutyl-propanoyl-L- isoleucyl-2-pyridylmethylamide (Formula C-6) Refer to Chart C.
- the compound cyclohexanecarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide; or cyclohexane-carbonyl-CVD-Ile-Amp may be prepared.
- PREPARATION 127 tert-Butyl-O-(4-quinolinyl)-glycolic carboxylate (Formula D-2) Refer to
- the residue is triturated with ether, the mixture filtered through Celite, and the solvent removed under reduced pressure.
- the residue is purified by sublimation at ca 0.1 Torr and 100° to yield 289 mg of the titled product as a feathery white solid.
- dichloromethane is added a solution of 32 mg of the titled product of Preparation 130 in 0.5 ml of dichloromethane.
- the resulting yellow solution is stirred for one hour, then 44 ⁇ L of diisopropylethylamine is added. After another 20 minutes, this mixture, which contains some precipiate, is added to 41.4 mg of 5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide (E-2).
- E-2 5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide
- CV-1 Assay (% Inhibition): 12% at 1 ⁇ M.
- CV-1 Assay (% Inhibition): 20% at 1 ⁇ M.
- the titled product of Preparation 132 is dissolved in 5-10 ml of newly prepared hydrochloric acid-saturated methanol (prepared by bubbling anhydrous hydrochloric acid into methanol for about twenty minutes). After 20-30 minutes, this mixture is concentrated in vacuo and the residue examined by high performance liquid chromatography to determine completion of the deprotection reaction.
- reaction is concentrated in vacuo to remove the N,N-dimethylformamide and the resulting residue dissolved in ethyl acetate and washed with sat. sodium carbonate.
- aqueous phase is re-extracted with ethyl acetate and the combined organic phases washed with saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo to yield 7.7 g brown gum.
- This material is purified by loading on a 46 ⁇ 4.6 cm silica gel flash column in ethyl acetate and eluting with 0.5 L each of 20%, 30%, 40%, 50%, and 60% ethyl acetate in hexane and 1.0 L each 66% and 70% ethyl acetate in hexane.
- the desired product (5.20 g) eluted at 70% ethyl acetate.
- Tert-butyloxycarbonyl-Ile (528 mg) is coupled to 8-aminoquinoline (288 mg) in 2 mL of dry N,N-dimethylformamide and 2.1 mL of N,N-diisopropylethylamine with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (972 mg) at room temperature.
- the extractive workup is as previously described in Preparation 132 and the resulting residue is loaded on a silica gel flash column and eluted with 5% methanol/94% chloroform/ 1 % acetic acid.
- One fraction contained pure product (177 mg); the rest were contaminated with unreacted 8-aminoquinoline.
- aqueous phase is extracted twice with ethyl acetate, the combined organics washed with water, and dried over sodium sulfate to give 262 mg crude extract.
- Half of this extract is purified on a 2 ⁇ 30 cm reverse phase C18 column, eluted with 15-50% CH3CN/0.1% trifluoroacetic acid in water; 21.2 mg titled product is isolated along with 18.1 mg (16%) of diacetylated compound.
- Tert-butyloxycarbonyl-Val (478 mg) is coupled to 2-aminomethyl-pyridine in 1.6 mL dry N,N-dimethylformamide and 2 mL N,N-diisopropylethylamine with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (942 mg) at room temperature.
- the extractive workup is as previously described in Preparation 132, and the resulting residue is loaded on a silica gel flash column and eluted with 3% methanol/94% chloroform/ 1 % acetic acid to yield pure titled product (826 mg).
- the titled product of Preparation 138 (183 mg) is deprotected with 2 mL hydrochloric acid/methanol for 20 min at room temperature, then concentrated in vacuo and monitored by high performance liquid chromatography. The residue is taken up in 0.5 mL dry N-N- dimethylformamide, 598 ⁇ L N,N-diisopropylethylamine and coupled to Tert-butyloxycarbonyl-Cha ⁇ [CH(Otert-butyldimethylsilyl)CH 2 ]Val-OH (240 mg) with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (238 mg) at room temperature overnight. Following an extractive workup as described above, 431 mg crude titled product is obtained; no purification is done.
- aqueous phase is extracted twice with ethyl acetate, the combined organic layers washed with water, and dried over sodium sulfate to give 272 mg crude product.
- Half of this material is purified on s 2 ⁇ 30 cm reverse-phase C18 column, eluted with 5-30% CH 3 CN/0.1 % trifluoroacetic acid in water; 22.4 mg titled product is isolated.
- CV-1 Assay (% Inhibition): 54% at lO ⁇ M.
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Abstract
Les peptides répondant à la formule (I): X1-C8-D9-E10-F11-G12-Z, et possédant au moins un monoester ou diester de O-phosphate, et leurs composés apparentés, sont utilisés pour inhiber un rétrovirus dans une cellule mammifère infectée par ledit rétrovirus.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US67950891A | 1991-04-04 | 1991-04-04 | |
US679508 | 1991-04-04 |
Publications (1)
Publication Number | Publication Date |
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EP0578745A1 true EP0578745A1 (fr) | 1994-01-19 |
Family
ID=24727186
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92910121A Withdrawn EP0578745A1 (fr) | 1991-04-04 | 1992-03-27 | Composes contenant du phosphore et servant d'inhibiteurs de retrovirus |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0578745A1 (fr) |
JP (1) | JPH06506463A (fr) |
AU (1) | AU1748792A (fr) |
MX (1) | MX9201546A (fr) |
WO (1) | WO1992017490A1 (fr) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
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US5643878A (en) * | 1991-09-12 | 1997-07-01 | Ciba-Geigy Corporation | 5-amino-4-hydroxyhexanoic acid derivatives |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
BR9306058A (pt) * | 1992-03-11 | 1997-11-18 | Narhex Ltd | Derivados de amina de hidrocarbonetos oxo- e hidroxi- substituidos |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
MXPA93002392A (es) | 1992-03-11 | 2005-02-04 | Narhex Ltd | Derivados amino de hidrocarburos-oxo e hidroxi-substituidos. |
US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
IL108459A0 (en) * | 1993-02-05 | 1994-04-12 | Opjohn Company | 4-Hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl [B] pyran-2-ones useful for treating infections due to hiv and other retroviruses |
IL129871A (en) | 1994-05-06 | 2003-11-23 | Pharmacia & Upjohn Inc | Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections |
US5965532A (en) | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
DK0966443T3 (da) | 1997-02-26 | 2009-03-09 | Pfizer | Heteroaryl-hexansyre amidderivater, deres fremstilling og deres anvendelse som selektive inhibitorer af MIP-1-alfa binding til dens CCR1 receptor |
US6100234A (en) | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
US6040145A (en) | 1997-05-07 | 2000-03-21 | Tufts University | Potentiation of the immune response |
EP1019494B1 (fr) | 1997-09-29 | 2007-03-21 | Point Therapeutics, Inc. | Stimulation de cellules hematopoietiques in vitro |
EA002822B1 (ru) * | 1997-12-17 | 2002-10-31 | Мерк Энд Ко., Инк. | Антагонисты рецептора интегрина |
AU770319C (en) | 1998-05-04 | 2004-11-25 | Point Therapeutics, Inc. | Hematopoietic stimulation |
KR100704814B1 (ko) | 1998-06-05 | 2007-04-10 | 포인트 써러퓨틱스, 인크. | 시클릭 보로프롤린 화합물 |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
US20030039661A1 (en) * | 2001-03-02 | 2003-02-27 | Teresa Aja | Methods, compositions and kits for preserving antigenicity |
MXPA04000337A (es) | 2001-07-10 | 2004-07-23 | Upjohn Co | Amindioles para tratamiento de enfermedad de alzheimer. |
-
1992
- 1992-03-27 JP JP4509356A patent/JPH06506463A/ja active Pending
- 1992-03-27 AU AU17487/92A patent/AU1748792A/en not_active Abandoned
- 1992-03-27 WO PCT/US1992/002238 patent/WO1992017490A1/fr not_active Application Discontinuation
- 1992-03-27 EP EP92910121A patent/EP0578745A1/fr not_active Withdrawn
- 1992-04-03 MX MX9201546A patent/MX9201546A/es not_active IP Right Cessation
Non-Patent Citations (1)
Title |
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See references of WO9217490A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1992017490A1 (fr) | 1992-10-15 |
JPH06506463A (ja) | 1994-07-21 |
AU1748792A (en) | 1992-11-02 |
MX9201546A (es) | 1993-02-01 |
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