EP0594586A1 - Inhibitoren der hiv-protease - Google Patents
Inhibitoren der hiv-proteaseInfo
- Publication number
- EP0594586A1 EP0594586A1 EP91903689A EP91903689A EP0594586A1 EP 0594586 A1 EP0594586 A1 EP 0594586A1 EP 91903689 A EP91903689 A EP 91903689A EP 91903689 A EP91903689 A EP 91903689A EP 0594586 A1 EP0594586 A1 EP 0594586A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- hydroxy
- alanyl
- oxo
- benzyl
- 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- Withdrawn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
- 239000004030 hiv protease inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract 2
- -1 amino-6-phenylhexanoyl-valyl valine methyl ester Chemical compound 0.000 claims description 58
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 28
- 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 12
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- WMRSMXAGHSKRHW-INIZCTEOSA-N (2S)-2-[amino(6-phenylhexanoyl)amino]-3-methylbutanamide Chemical compound CC(C)[C@@H](C(=O)N)N(C(=O)CCCCCC1=CC=CC=C1)N WMRSMXAGHSKRHW-INIZCTEOSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000031886 HIV Infections Diseases 0.000 claims description 3
- KHDJJHQOPWRTEH-BUQFVWSMSA-N benzyl N-[(2S)-1-[[(2S,3S)-6-[[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-5-benzyl-3-hydroxy-6-oxo-1-phenylhexan-2-yl]amino]-1-oxopropan-2-yl]carbamate Chemical compound C(=O)(OCC1=CC=CC=C1)N[C@@H](C)C(=O)N[C@H]([C@H](CC(C(=O)N[C@H](C(C)C)C(=O)N)CC1=CC=CC=C1)O)CC1=CC=CC=C1 KHDJJHQOPWRTEH-BUQFVWSMSA-N 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- UZWLFXQNUWKWLJ-BRELJPODSA-N benzyl N-[(2S)-1-[[(2S)-1-[[(2S,3S)-6-[[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-5-benzyl-3-hydroxy-6-oxo-1-phenylhexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamate Chemical compound C(=O)(OCC1=CC=CC=C1)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H]([C@H](CC(C(=O)N[C@H](C(C)C)C(=O)N)CC1=CC=CC=C1)O)CC1=CC=CC=C1 UZWLFXQNUWKWLJ-BRELJPODSA-N 0.000 claims description 2
- LVNIPNSGVDFGFP-WLAADAIHSA-N benzyl N-[(2S)-1-[[(2S,3S)-5-[[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]-3-hydroxy-1-phenyloctan-2-yl]amino]-1-oxopropan-2-yl]carbamate Chemical compound CCCC(C[C@@H]([C@H](CC1=CC=CC=C1)NC(=O)[C@H](C)NC(=O)OCC2=CC=CC=C2)O)C(=O)N[C@H](C(C)C)C(=O)N LVNIPNSGVDFGFP-WLAADAIHSA-N 0.000 claims description 2
- XVXUSQYWWIBVCO-WNTFFZHHSA-N benzyl N-[(2S,4S,5S)-8-[amino-[(2R)-1-hydroxy-3-methylbutan-2-yl]amino]-4,7-dibenzyl-5-hydroxy-3,8-dioxooctan-2-yl]carbamate Chemical compound C(=O)(OCC1=CC=CC=C1)N[C@@H](C)C(=O)[C@H]([C@H](CC(C(=O)N([C@H](C(C)C)CO)N)CC1=CC=CC=C1)O)CC1=CC=CC=C1 XVXUSQYWWIBVCO-WNTFFZHHSA-N 0.000 claims description 2
- AUJGDYRWXSOUHG-DIZVPCGUSA-N benzyl N-[2-[[(2S)-1-[[(2S,3S,5R)-5-benzyl-6-(benzylamino)-3-hydroxy-6-oxo-1-phenylhexan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxo-1-phenylethyl]carbamate Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)[C@H](C[C@@H](CC2=CC=CC=C2)C(=O)NCC3=CC=CC=C3)O)NC(=O)C(C4=CC=CC=C4)NC(=O)OCC5=CC=CC=C5 AUJGDYRWXSOUHG-DIZVPCGUSA-N 0.000 claims description 2
- IQXWYIBSDZTYOM-MSMMDESQSA-N tert-butyl (2S,3S)-6-[amino-[(2R)-1-hydroxy-3-methylbutan-2-yl]amino]-2,5-dibenzyl-3-hydroxy-6-oxohexanoate Chemical compound C(C)(C)(C)OC(=O)[C@H]([C@H](CC(C(=O)N([C@H](C(C)C)CO)N)CC1=CC=CC=C1)O)CC1=CC=CC=C1 IQXWYIBSDZTYOM-MSMMDESQSA-N 0.000 claims description 2
- 208000037357 HIV infectious disease Diseases 0.000 claims 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims 2
- PTZYISYPCDPOTL-ACBHZAAOSA-N (2S)-2-[amino-[4-hydroxy-2-(2-methylpropyl)-6-phenylhexanoyl]amino]-3-methylbutanamide Chemical compound NN([C@@H](C(C)C)C(=O)N)C(C(CC(CCC1=CC=CC=C1)O)CC(C)C)=O PTZYISYPCDPOTL-ACBHZAAOSA-N 0.000 claims 1
- JGYMZKROXQDIRE-YKRJCGNBSA-N [(2R)-2-[[(4S,5S)-4-hydroxy-2-methyl-6-phenyl-5-[[(2S)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-methylbutyl] acetate Chemical compound CC(C(=O)N[C@H](C(C)C)COC(C)=O)C[C@@H]([C@H](CC1=CC=CC=C1)NC([C@@H](NC([C@@H](NC(=O)OCC1=CC=CC=C1)C)=O)C)=O)O JGYMZKROXQDIRE-YKRJCGNBSA-N 0.000 claims 1
- VOSUPDOPDSAAPZ-HXVVHCTFSA-N benzyl N-[(2S)-1-[[(2S,3S)-5-[[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamoyl]-3-hydroxy-7-methyl-1-phenyloctan-2-yl]amino]-1-oxopropan-2-yl]carbamate Chemical compound C(=O)(OCC1=CC=CC=C1)N[C@@H](C)C(=O)N[C@H]([C@H](CC(C(=O)N[C@H](C(C)C)C(=O)N)CC(C)C)O)CC1=CC=CC=C1 VOSUPDOPDSAAPZ-HXVVHCTFSA-N 0.000 claims 1
- ONBNNFCSZAXJKP-CDDJFQJMSA-N benzyl N-[(2S,4S,5S,7R)-4-[amino(phenyl)methyl]-7-benzyl-8-(benzylamino)-5-hydroxy-3,8-dioxooctan-2-yl]carbamate Chemical compound C[C@@H](C(=O)[C@H]([C@H](C[C@@H](CC1=CC=CC=C1)C(=O)NCC2=CC=CC=C2)O)C(C3=CC=CC=C3)N)NC(=O)OCC4=CC=CC=C4 ONBNNFCSZAXJKP-CDDJFQJMSA-N 0.000 claims 1
- ISFBTANONQFYNV-LDMSUSSSSA-N methyl (2R)-2-[[(4S,5S)-2-benzyl-4-hydroxy-6-phenyl-5-[[(2S)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-methylbutanoate Chemical compound COC([C@H](NC(C(C[C@@H]([C@H](CC1=CC=CC=C1)NC([C@@H](NC([C@@H](NC(=O)OCC1=CC=CC=C1)C)=O)C)=O)O)CC1=CC=CC=C1)=O)C(C)C)=O ISFBTANONQFYNV-LDMSUSSSSA-N 0.000 claims 1
- TWWNCWSEBSUGAC-RDEHQKHQSA-N methyl (2R)-2-[amino-[(2S,5S,7S)-2,5-dibenzyl-4-hydroxy-6-oxo-7-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]octanoyl]amino]-3-methylbutanoate Chemical compound COC([C@H](N(C([C@H](CC([C@H](CC1=CC=CC=C1)C([C@@H](NC([C@@H](NC(=O)OCC1=CC=CC=C1)C)=O)C)=O)O)CC1=CC=CC=C1)=O)N)C(C)C)=O TWWNCWSEBSUGAC-RDEHQKHQSA-N 0.000 claims 1
- KOOHFJHIRIZHEB-GJNYURASSA-N methyl (2R)-2-[amino-[(4S,5S,7S)-2,5-dibenzyl-4-hydroxy-6-oxo-7-(phenylmethoxycarbonylamino)octanoyl]amino]-3-methylbutanoate Chemical compound COC([C@H](N(C(C(C[C@@H]([C@H](CC1=CC=CC=C1)C([C@@H](NC(=O)OCC1=CC=CC=C1)C)=O)O)CC1=CC=CC=C1)=O)N)C(C)C)=O KOOHFJHIRIZHEB-GJNYURASSA-N 0.000 claims 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims 1
- 229960002555 zidovudine Drugs 0.000 claims 1
- 208000030507 AIDS Diseases 0.000 abstract description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 abstract 1
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 38
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 16
- 108091005804 Peptidases Proteins 0.000 description 15
- 239000004365 Protease Substances 0.000 description 15
- 102000004196 processed proteins & peptides Human genes 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 108010010369 HIV Protease Proteins 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000002253 acid Chemical class 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000001177 retroviral effect Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- NWYYWIJOWOLJNR-UHFFFAOYSA-N 2-Amino-3-methyl-1-butanol Chemical compound CC(C)C(N)CO NWYYWIJOWOLJNR-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
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- 239000000843 powder Substances 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- XDEHMKQLKPZERH-BYPYZUCNSA-N (2s)-2-amino-3-methylbutanamide Chemical compound CC(C)[C@H](N)C(N)=O XDEHMKQLKPZERH-BYPYZUCNSA-N 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- 108010021889 valylvaline Proteins 0.000 description 4
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- AKJQMHRBAMMCBR-VYRBHSGPSA-N tert-butyl N-[(2S)-3-hydroxy-1-phenylhept-6-en-2-yl]carbamate Chemical compound C1(=CC=CC=C1)C[C@@H](C(CCC=C)O)NC(=O)OC(C)(C)C AKJQMHRBAMMCBR-VYRBHSGPSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
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- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- 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
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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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- 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
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals .
- Rous sarcoma virus RSV
- murine leukemia virus MMV
- mouse mammary tumor virus MMTV
- feline leukemia virus FeLV
- bovine leukemia virus BLV
- Mason-Pfizer monkey virus MPMV
- SSV simian sarcoma virus
- SAIDS simian acquired immunodeficiency syndrome
- the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.
- the HTLV and HIV have been especially well characterized. Although diverse in detail, all retroviruses are rather similar in overall structure.
- the extracellular virus particle is composed of an outer membrane studded with viral glycoproteins, a core of structural proteins, and a genome of single stranded ribonucleic acid.
- the retroviral genome has a distinctive regional organization, referred to as the 5'- ⁇ a ⁇ -pol-env-3 ' structure, wherein the gag region encodes the core structural proteins, the pol region encodes certain critical viral enzymes such as reverse transcriptase, integrase and protease, and the env region encodes the envelope glycoproteins .
- Viral replication occurs only within host cells and is dependent upon host cellular functions . Critical to this replication is the production of functional viral proteins. Protein synthesis is accomplished by translation of the open reading frames into polyprotein constructs, corresponding to the gag, pol and env reading frames, which are processed, at least in part, by a viral protease into the functional proteins.
- the proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus .
- retroviruses which lack the protease or contain a mutated form of it, lack infectivity. See Katoh et al., Virolo ⁇ v. 145, 280-92(1985), Crawford, et al. , £_. Virol . , 53, 899-907(1985) and Debouk, et al. , Proc. Na l. Acad. Sci. USA. 84, 8903-6(1987) . Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.
- This invention comprises compounds, hereinafter, of the formula (I) , which inhibit the retroviral protease of HIV-1, and are useful for treating Acquired Immunodeficiency Syndrome (AIDS) .
- AIDS Acquired Immunodeficiency Syndrome
- This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
- This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) .
- A is BocNH, CbzNH, H, R'R"N, R"CONR*, or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R" or R"CO;
- C and D are the same or different and are Ala, ⁇ -Ala, D-
- X is Ala, lie, Leu, Val
- Y is Ala, lie, Leu, Val or is a covalent bond
- Z is CO2R"", CONR'R"", COR 1 , CH2OR”", CH2 ⁇ C(0)R” or H, or if e is 0 and Y is a covalent bond, Z is OR"" or NR'R""; b, c and e are each independently 0 or 1, provided that c and e are not simultaneously 0;
- Rl is independently , C ⁇ _5 lk, C3_5alkenyl or benzyl;
- R' and R" are H or C__5 lk
- R" is H, C ⁇ -_5Al , C3_gcycloalkyl, (CH 2 ) n C6H5, (CH 2 ) n C5H4N, (CH 2 ) n OH, (CH 2 ) n NH2, or (CH 2 ) n NHC (NH)NH ; and pharmaceutically acceptable salts thereof; provided that if b and e are 0, Y is a covalent bond and D is Val, then Ri is not isobutyl.
- the compounds of this invention are more potent than those reported previously and have favorable pharmaceutical properties.
- Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
- A comprises the terminal amino group of the peptide
- Z comprises the terminal carboxyl group of the peptide.
- the terminal residues of the peptide are "des-amino" and “descarboxy” amino acids respectively.
- A comprises the terminal amino group of the residue C; or, when b is 0, to D.
- the amino group of M is substituted by an acyl or alkyl group, as specially provided by A in formula (I) .
- Z comprises the terminal carboxyl group of the amino acid residue corresponding to Y; or when Y is a covalent bond, to X.
- Y is a covalent bond and d and e are 0, the terminal carboxyl group of M is substituted by Z as specially provided in formula (I) .
- the amino terminus is on the left and the carboxy terminus is on the right.
- all chiral amino acids (AA) are assumed to be of the L absolute configuration.
- (4'R a )Phe refers to phenylalanine substituted in the 4 position of the phenyl ring by R a .
- Boc refers to the t- butyloxycarbonyl radical
- Cbz refers to the carbobenzyloxy radical
- BrZ refers to ' the o-bromobenzyloxycarbonyl radical
- Clz is the p-chlorocarbobenzyloxy radical
- CI2Z refers to the 2,4-dichlorocarbobenzyloxy radical
- Bzl refers to the benyzl radical
- Ac refers to acetyl
- Alk or C ⁇ -5Alk refers to C ] __5alkyl
- Ph refers to phenyl
- DCC refers to dicyclohexyl- carbodiimide
- DMAP refers to dimethylaminopyridine
- HOBT refers to 1-hydroxybenzotriazole
- NMM is N-methylmorpholine
- DTT is dithiothreitol
- EDTA is ethylenediamine tetraacetic acid
- HF hydrofluoric acid
- TFA trifluoroacetic acid
- C ⁇ _5al yl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl and isopentyl. As used herein in the compounds of this invention.
- Especially preferred compounds of this invention are di-, tri- and tetrapeptides such as A-C-D-M-X-Y-Z, A-C-D-M-X-Z, A-C-D-M-Z, A-D-M-X-Y-Z, A-D-M-X-Z, A-D-M-Z and A-M-X-Y-Z.
- X and Y are suitably valine.
- C and D are suitably alanine.
- C is Ala and X is Val.
- Ri is H, Ci-5alkyl, allyl or benzyl. In one preferred embodiment Ri is H, C ⁇ _5alkyl, allyl or benzyl.
- Ri is H, C ⁇ _5alkyl, allyl or benzyl.
- i is propyl.
- Z is CO2CH3,
- Representative compounds of this invention are: (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl-valyl valine methyl ester;
- Other methods are disclosed by Holladay j ⁇ t. al ⁇ . J. Med. Chem.. 30, 374-83(1987) and Kempf, D., J. Qr ⁇ . Chem , 51, 21, 3921-26(1986) .
- the amino acids or modified amino acids of this invention are generally available commercially or are prepared by conventional methods of organic chemistry. Solution synthesis of the peptides is accomplished using routine methods for coupling the appropriate amino acid residues and optionally removing any protective groups..
- a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N 1 dicyclohexyl carbodiimide (DCC) , optionally in the presence of catalysts such as 1- hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP) .
- a suitable carbodiimide coupling agent such as N, N 1 dicyclohexyl carbodiimide (DCC)
- catalysts such as 1- hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP) .
- HOBT 1- hydroxybenzotriazole
- DMAP dimethylamino pyridine
- a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran (THF) , in the presence of a base, such as N-methyl morpholine, DMAP or a trialkyl amine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or peptide.
- the peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques .
- the protecting groups may be removed as hereinbefore described, such as by hydrogenation in the presence of a palladium or platinum catalyst, treatment with sodium in liquid ammonia, hydrofluoric acid or alkali.
- Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be converted to carboxylic acids by treatment with an alkali metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an aqueous alcoholic solution. The acids may be converted to other esters via an activated acyl intermediate as previously described.
- the amides and substituted amides of this invention are prepared from carboxylic acids of the peptides in much the same manner. Thus, ammonia or a substituted amine may be reacted with an activated acyl intermediate to produce the amide.
- Use of coupling reagents, such as DCC is convenient for forming substituted amides from the carboxylic acid itself and a suitable amine.
- the methyl esters of this invention may be converted to the amides, or substituted-amides, directly by treatment with ammonia, or a substituted amine, in methanol solution.
- a methanol solution of the methyl ester of the peptide is saturated with ammonia and stirred in a pressurized reactor to yield the simple carboxamide of the peptides.
- Carboxamides are preferred embodiments of this invention due their enhanced stability relative to esters . If the final peptide, after it has been deprotected, contains a basic group, an acid addition salt may be prepared.
- Acid addition salts of the peptides are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
- the acetate salt form is especially useful.
- cationic salts may be prepared.
- the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation.
- Cations such as Na + , K + , Ca ++ and NH4 " are examples of cations present in pharmaceutically acceptable salts .
- Certain of the compounds form inner salts or zwitterions which may also be acceptable.
- the compounds of formula (I) wherein M is -HNCHR; ] _R -, are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatmen .
- the method of treatment comprises the administration orally, parenterally, buccally, trans-dermally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier.
- Dosage units- of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection.
- protease inhibiting properties of the peptides of this invention are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 0.1 nM to about 1.0 ⁇ M.
- the following table is representative of the inhibition constants of these peptides.
- compositions of the peptides of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration.
- Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid, formulation is generally a buffered, isotonic, aqueous, solution.
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- a preferred composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier.
- the liposome may be formed by dispersion of the peptides in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization.
- a suitable method of making such compositions is more fully disclosed in copending Application Serial No. 06/763,484 and is incorporated herein by reference.
- Such a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
- CD-4 T-cell glycoprotein or a derivative thereof, such as sCD-4 (soluble CD-4), which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV) .
- sCD-4 soluble CD-4
- HAV human immunodeficiency virus
- these peptides may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
- Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- The'amount of solid carrier varies but, preferably, will be between about 20 g to about 1 g per dosage unit.
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
- Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
- a pulverized powder of the peptides of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
- excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
- the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
- Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention.
- anti-viral agents examples include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen.
- Nucleoside analogues which include 2 ' ,3 '-dideoxycytidme (ddC) , 2 ' ,3 '-dideoxyadenine (ddA) and 3 '-azido-2 ' ,3 '-dideoxythymide (AZT) , are especially useful.
- AZT is one preferred agent.
- pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting peptide -of this invention and a pharmaceutically acceptable carrier.
- the cells were lysed by sonication and insoluble material was removed by centrifugation at 15,000 x g av, for 15 mi .
- the clarified supernatant was then brought to 40% of saturation with ammonium sulfate.
- This suspension was stirred at room temperature for 30 min. and then centrifuged as above.
- the resulting precipitate was redissolved/resuspended in a minimal volume of 20 mM Tris-HCl, pH 7.5; 200 mM NaCl; 0.1 mM each DTT and EDTA.
- the sample was centrifuged again before application (in 5 ml aliquots) to a Beckman TSK G2000SW preparative HPLC gel filtration column (2.1 cm x 60 cm.) .
- the column was equilibrated in the same buffer at a flow rate of 4 ml/min.
- the effluent of the column was monitored at 280 nm and 1 min. fractions collected.
- the rHIVPRT recombinant HIV protease
- the protease was N85-95% pure.
- By immunoblot analysis >90% of the immunoreactive material was precipitated at the ammonium sulfate step.
- activity assay the highest peak of activity was found in the fractions collected at 45 and 46 minutes. Analysis of the TSK column fractions by RP- HPLC and SDS-PAGE indicated that the majority of the 11,000 Mr protein is also found in fractions 45 and 46.
- the activity itself cannot be used to obtain reliable recovery data as it is influenced by high salt, i.e., with increasing salt, increasing levels of activity were obtained. Thus, with each step in the purification, more total activity was recovered than was started with.
- the overall yield of rHIVPRT was Nl mg from a 50 gm E_ ⁇ _ coli cell pellet.
- MENDT buffer 50 mM Mes (pH 6.0; 2- (N-morpholino)ethanesulfonic acid), 1
- reaction mixtures 37°C were quenched after 10-20 minutes • with an equal volume of cold 0.6 N trichloroacetic acid, and, following centrifugation to remove precipitated material, peptidolysis products were analyzed by reverse phase HPLC
- N-methyl piperidine (24.4 ml, 0.206 mol) was added via addition funnel to a stirring suspension of N,0- dimethylhydroxylamine hydrochloride (19.56 g, 0.2 mol) in methylene chloride (118 ml) at 0°C, forming a clear solution
- Boc-phenylalanine (53 g, 0.2 mol), THF (230 ml) and methylene chloride (900 ml) were combined and cooled to - 20°C, and N-methyl piperidine (24.4 ml) was added dropwise with stirring.
- Methyl chloroformate (15.5 ml, 0.2 mol) was then added rapidly via addition funnel with good stirring, the temperature being maintained below -10°C.
- the thick black mixture was cooled to 0°C and saturated aqueous NaHS ⁇ 3 (75 m l) was added. After 15 min stirring, the resulting white mixture was filtered through Celite®, the aqueous layer was separated and extracted with ether. The combined organic layers were washed with water and concentrated to a foam (6.9 g) .
- the resulting crude 4-acetoxy acids were dissolved in 100 ml methanol and sodium methoxide (ca. 10 g) was added. The mixture was stirred at 25°C for two days then at 60°C for 18 hr. The thick mixture was concentrated, diluted with methylene chloride and extracted with 10% HCl. The aqueous layers were extracted twice with methylene chloride.
- Example 1(e) To a solution of the lactone of Example 1(e) (.175 g, .507 mmol) in methanol (5 mL) was introduced 10% Pd on activated carbon (.020 g) . Hydrogen gas was bubbled through the solution for 1 hr and the solution was then maintained under a hydrogen atmosphere for 12 hr. The mixture was filtered through a pad of Celite with methanol and the solvents evaporated to give the titled compound as a white solid (.166 g, 94%) .
- Example 1(f) The lactone of Example 1(f) (.166 g, .45 mmol) was dissolved in 1,4-dioxane (2 mL) and distilled water (1 mL) . To this cloudy solution was added 1 N NaOH (.523 mL, 1.1 eq.)
- the white foam was stirred in dimethylformamide (1.5 L) at 25°C and to this solution was added tert-butyl dimethylsilylchloride (.407 g, 5 eq.) and imidazole (.367 g, 10 eq.) . The mixture was allowed to stir under an argon
- step 1(e) substituting in step 1(e), in place of allyl bromide, either: (a) methyl iodide, (b) benzyl bromide, (c) methallyl bromide or (d) isobutyl bromide, the following compounds were prepared:
- Example 1(g) To a solution of the acid of Example 1(g) (.080 g, .167 mmol) in tetrahydrofuran (1 mL) at -40°C under argon was added N-methyl morpholine (.027 mL, .25 mmol) and isobutyl chloroformate (.022 mL, .167 mmol) . After stirring for 15 min at -40°C, N-methyl orpholine (.027. mL, .00025 mole) and Valine valine methyl ester hydrochloride (.049 g, .183 mmol) were added. The mixture was warmed to 25°C and allowed to stir under argon for 14 hr.
- the mixture was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
- the organic layer was dried over magnesium sulfate, filtered and evaporated to a white semi-solid residue.
- Example 4(a) The compound of Example 4(a) (.073 g, .106 mmol) was stirred in neat trifluoroacetic acid (1 mL) for 5 min, diluted with methanol, and treated with 2 drops of concentrated hydrochloric acid. The solvents were removed in vacuo to give the hydrochloride salt as a white foam(.071 g) .
- the reaction was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
- the organic layer was dried over magnesium sulfate, filtered,and evaporated to a white solid which was chromatographed (silica gel, 40:1 dichloromethane:methanol) to give the titled compound as a white solid (.020 g, 45%) .
- Example 4(b) The compound of Example 4(b) (.020 g, .0251 mmol) was dissolved in 1 mL of neat trifluoroacetic acid and stirred for 10 min. The solution was diluted with dichloromethane and shaken with 5% aqueous sodium bicarbonate. The organic layer was removed and washed with water. The solvents were removed in vacuo and the resultant white solid was triturated with diethyl ether to give the titled compound as a white foam (.013 g, 76%) . NMR (DMSO-d 6 ) : ⁇ 8.18 (1H, d) , 7.61(1H, d) , 7.53 (1H, d) ,
- Example 4 Using the procedure of Example 4, the carboxyl group of the compound of Example 3 was reacted with the hydrochloride of valinamide, the amino group was deprotected and acylated with Cbz-alanine, and the t-butyldimethylsilyl-protecting group was removed to yield the titled compound.
- NMR (DMSO-d6) ⁇ 7.56(2H, dd) , 7.37(6H, m) , 7.20 (5H, m) , 6.98(1H, s) , 5.67(1H, m) , 5.05-4.88 (4H, m) , 4.09(2H, dd) ,
- the carboxyl group of the compound of Example 2 (a) is reacted with the hydrochloride of valine methyl ester, valyl-valine methyl ester, valinamide, valyl-valinamide, valinol or valyl-valinol, the amino group is deprotected and acylated with Cbz-alanine, Cbz-alanyl- alanine, Cbm-alanine or propanoic acid, and the t- butyldimethylsilyl-protecting group is removed to yield the following specific compounds.
- Valinols are acetylated in conventional fashion by treatment with triethylamine and acetic anhydride, acids are produced by hydrolysis with aq. methanolic potassium hydroxide of the corresponding methyl 5 esters. Carbobenzyloxy groups are removed by conventional hydrogenolysis with 5% palladium on carbon.
- Phosphatidylcholine (1.4 g) and phosphatidylglycerol ( .6g) are dissolved in 300 ml of a 20% methanol in chloroform solvent and evaporated to dryness.
- a solution of the peptide (30 mg in 200 ml of phosphate buffered saline) is added to the dry phospholipid film which is allowed to equilibrate at room temperature for 1-2 hr.
- the liposome dispersion formed is then vortexed to insure uniform mixing.
- the resulting suspension is extruded through a 0.2 ⁇ polycarbonate filter five times to produce a uniform size distribution. If necessary the suspension can be dialysed or ultracentrifuged to remove non-encapsulated peptide.
- Phosphate buffered saline pH 7.4 is added in small aliquots with vortexing to achieve a concentration of 200 mg of liposomal gel per ml. Liposomes form spontaneously. This procedure produces 5 g of liposomal suspension. A standard dosage unit is 1 g of liposomal suspension.
- a preparation which contains 25 mg of a peptide of this invention is prepared as follows: 25 mg of the peptide is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions in to a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume.
- D5W dextrose in water
- This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion.
- a capsule for oral administration is prepared by mixing and milling 35 mg of the peptide with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
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Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US469891 | 1983-02-25 | ||
US46266990A | 1990-01-09 | 1990-01-09 | |
US462669 | 1990-01-09 | ||
US46989190A | 1990-01-23 | 1990-01-23 | |
PCT/US1991/000178 WO1991010442A1 (en) | 1990-01-09 | 1991-01-09 | Hiv protease inhibitors |
Publications (2)
Publication Number | Publication Date |
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EP0594586A1 true EP0594586A1 (de) | 1994-05-04 |
EP0594586A4 EP0594586A4 (en) | 1994-08-17 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP9191903689A Withdrawn EP0594586A4 (en) | 1990-01-09 | 1991-01-09 | Hiv protease inhibitors |
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EP (1) | EP0594586A4 (de) |
JP (1) | JPH05503703A (de) |
WO (1) | WO1991010442A1 (de) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2055685A1 (en) * | 1990-11-19 | 1992-05-20 | Samuel L. Graham | Hiv protease inhibitors having polyether substituents |
US5436339A (en) * | 1991-03-06 | 1995-07-25 | Abbott Laboratories | Process for the preparation of a substituted diaminoalcohol |
PT100865A (pt) * | 1991-09-11 | 1994-01-31 | Smithkline Beckman Corp | Isosteros de peptido contendo um heterociclo, processo de preparacao dos mesmos seus intermediarios, uso e composicoes farmaceuticas |
DE4215874A1 (de) * | 1992-05-14 | 1993-11-18 | Bayer Ag | Dithiolanylglycinhaltige HIV-Proteaseinhibitoren vom Hydroxyethylenisostertyp |
US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
ES2068739B1 (es) * | 1993-01-21 | 1995-11-01 | Smithkline Beecham Corp | Inhibidores retrovirables de proteasas. |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
PT708085E (pt) * | 1994-10-19 | 2002-11-29 | Novartis Ag | Eteres antivirais de isosteros de substrato de aspartato protease |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0337714A2 (de) * | 1988-04-12 | 1989-10-18 | Merck & Co. Inc. | HIV-Protease-Inhibitoren zur Behandlung von AIDS |
EP0352000A2 (de) * | 1988-07-08 | 1990-01-24 | Smithkline Beecham Corporation | Retrovirale, Protease bindende Peptide |
EP0386611A2 (de) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Aminosäure-Derivate |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8322414D0 (en) * | 1983-08-19 | 1983-09-21 | Szelke M | Renin inhibitors |
-
1991
- 1991-01-09 WO PCT/US1991/000178 patent/WO1991010442A1/en active Search and Examination
- 1991-01-09 EP EP9191903689A patent/EP0594586A4/en not_active Withdrawn
- 1991-01-09 JP JP3503872A patent/JPH05503703A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0337714A2 (de) * | 1988-04-12 | 1989-10-18 | Merck & Co. Inc. | HIV-Protease-Inhibitoren zur Behandlung von AIDS |
EP0352000A2 (de) * | 1988-07-08 | 1990-01-24 | Smithkline Beecham Corporation | Retrovirale, Protease bindende Peptide |
EP0386611A2 (de) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Aminosäure-Derivate |
Non-Patent Citations (2)
Title |
---|
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA. vol. 86 , December 1989 , WASHINGTON US pages 9752 - 9756 G.B.DREYER ET AL 'Inhibition of HIV 1 protease in vitro; Rational design of substrate analogue inhibitors' * |
See also references of WO9110442A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1991010442A1 (en) | 1991-07-25 |
JPH05503703A (ja) | 1993-06-17 |
EP0594586A4 (en) | 1994-08-17 |
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