WO1993019059A1 - Antiviral peptides - Google Patents
Antiviral peptides Download PDFInfo
- Publication number
- WO1993019059A1 WO1993019059A1 PCT/EP1993/000597 EP9300597W WO9319059A1 WO 1993019059 A1 WO1993019059 A1 WO 1993019059A1 EP 9300597 W EP9300597 W EP 9300597W WO 9319059 A1 WO9319059 A1 WO 9319059A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- compound
- group
- hydroxy
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title description 7
- 230000000840 anti-viral effect Effects 0.000 title description 5
- 102000004196 processed proteins & peptides Human genes 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 36
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 27
- 125000003118 aryl group Chemical group 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 206010038997 Retroviral infections Diseases 0.000 claims abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 239000011737 fluorine Substances 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 238000011321 prophylaxis Methods 0.000 claims abstract description 6
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 5
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims abstract 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 50
- -1 R11 is H Chemical group 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 15
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- YUAQOAMSIBZOSM-LYXINOJLSA-N tert-butyl n-[(2r,3s,5s)-5-benzyl-3-hydroxy-6-[[(2s)-1-(3-imidazol-1-ylazetidin-1-yl)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound C([C@H]([C@@H](O)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CC(C1)N1C=NC=C1)CC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 YUAQOAMSIBZOSM-LYXINOJLSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- VHLOQUQGTBOALD-YTQWTBANSA-N tert-butyl n-[(2r,3s,5s)-5-benzyl-3-hydroxy-6-[[(2s)-1-(4-imidazol-1-ylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound C([C@H]([C@@H](O)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC(CC1)N1C=NC=C1)CC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 VHLOQUQGTBOALD-YTQWTBANSA-N 0.000 claims description 4
- 125000006192 3-phenylprop-2-enyl group Chemical group [H]\C(=C(\[H])C([H])([H])*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- YOHNPWQCDUNXJA-UWVYSXLVSA-N tert-butyl n-[(2s,3r,5s)-5-[(4-chlorophenyl)methyl]-3-hydroxy-6-[[(2s)-1-(3-imidazol-1-ylazetidin-1-yl)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CC(C1)N1C=NC=C1)CC=1C=CC(Cl)=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 YOHNPWQCDUNXJA-UWVYSXLVSA-N 0.000 claims description 3
- PCQXVCCCAGSMBW-PEBYJJCOSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-5-[[(2s)-1-(4-imidazol-1-ylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl]carbamoyl]-1,8-diphenyloct-7-en-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC(CC1)N1C=NC=C1)C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C=CC1=CC=CC=C1 PCQXVCCCAGSMBW-PEBYJJCOSA-N 0.000 claims description 3
- DDLFESZLXFANDD-UAMZLAIYSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(4-imidazol-1-ylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[[4-(trifluoromethoxy)phenyl]methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC(CC1)N1C=NC=C1)CC=1C=CC(OC(F)(F)F)=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 DDLFESZLXFANDD-UAMZLAIYSA-N 0.000 claims description 3
- IZWAQBCPOXQRRH-WKJCSOSYSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s,3s)-1-(4-imidazol-1-ylpiperidin-1-yl)-3-methyl-1-oxopentan-2-yl]amino]-6-oxo-1-phenyl-5-[[4-(trifluoromethoxy)phenyl]methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1CCC(CC1)N1C=NC=C1)CC=1C=CC(OC(F)(F)F)=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 IZWAQBCPOXQRRH-WKJCSOSYSA-N 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003566 oxetanyl group Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 229910052799 carbon Inorganic materials 0.000 abstract description 4
- 230000001177 retroviral effect Effects 0.000 abstract description 4
- 108091005804 Peptidases Proteins 0.000 abstract description 3
- 239000004365 Protease Substances 0.000 abstract description 3
- 102000035195 Peptidases Human genes 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 66
- 239000000047 product Substances 0.000 description 59
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- 238000002360 preparation method Methods 0.000 description 49
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 229960001866 silicon dioxide Drugs 0.000 description 26
- 238000004587 chromatography analysis Methods 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 22
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 238000000746 purification Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 13
- 241000725303 Human immunodeficiency virus Species 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
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- 238000001704 evaporation Methods 0.000 description 8
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- 125000003277 amino group Chemical group 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
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- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- HSPKIXPRSRGOQK-UHFFFAOYSA-N isoquinolin-5-ylmethanol Chemical compound N1=CC=C2C(CO)=CC=CC2=C1 HSPKIXPRSRGOQK-UHFFFAOYSA-N 0.000 description 1
- VLONTUPZTAEOIH-UHFFFAOYSA-N isoquinolin-7-ylmethanol Chemical compound C1=CN=CC2=CC(CO)=CC=C21 VLONTUPZTAEOIH-UHFFFAOYSA-N 0.000 description 1
- ILRSABOCKMOFGW-UHFFFAOYSA-N isoquinoline-5-carbaldehyde Chemical compound N1=CC=C2C(C=O)=CC=CC2=C1 ILRSABOCKMOFGW-UHFFFAOYSA-N 0.000 description 1
- QEAGQILEKLFCEK-UHFFFAOYSA-N isoquinoline-7-carbaldehyde Chemical compound C1=CN=CC2=CC(C=O)=CC=C21 QEAGQILEKLFCEK-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- QMLWSAXEQSBAAQ-UHFFFAOYSA-N oxetan-3-ol Chemical compound OC1COC1 QMLWSAXEQSBAAQ-UHFFFAOYSA-N 0.000 description 1
- 150000002924 oxiranes Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical class [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- WTTIBCHOELPGFK-LBPRGKRZSA-N r82150 Chemical class C1N(CC=C(C)C)[C@@H](C)CN2C(=S)NC3=CC=CC1=C32 WTTIBCHOELPGFK-LBPRGKRZSA-N 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- HQMYWQCBINPHBB-MRVPVSSYSA-N tert-butyl (2r)-2-methyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@@H]1CC(=O)CCN1C(=O)OC(C)(C)C HQMYWQCBINPHBB-MRVPVSSYSA-N 0.000 description 1
- MMVDGCVHNGWMJO-DGEZQFQFSA-N tert-butyl N-[(2R,3S,5S)-5-benzyl-3-hydroxy-6-[[(2S)-3-methyl-1-oxo-1-[4-(1,2,4-triazol-4-yl)piperidin-1-yl]butan-2-yl]amino]-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound C([C@H]([C@@H](O)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC(CC1)N1C=NN=C1)CC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 MMVDGCVHNGWMJO-DGEZQFQFSA-N 0.000 description 1
- ZJTYRNPLVNMVPQ-LBPRGKRZSA-N tert-butyl n-[(2s)-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CC1=CC=CC=C1 ZJTYRNPLVNMVPQ-LBPRGKRZSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to certain peptide derivatives containing a heterocyclic group which are useful in the treatment or prophylaxis of human
- the human immunodeficiency virus (HIV), a
- opportunistic infections e.g. pneumocystis carinii, human cytomegalovirus, or Candida
- cancers such as Kaposi's sarcoma.
- Loss of cells, particularly CD4 + lymphocytes, following infection with HIV is an
- monocyte/macrophage lineage with HIV also contributes to the observed pathology.
- successful infection of CD4 + cells by HIV is a key step in the disease process.
- HIV is a retrovirus; it encodes its genetic information in RNA, which is converted into DNA after the virus enters the host cell.
- An essential step in the retroviral replication cycle is the processing of an initial polypeptide precursor into mature structural and replicative proteins. This processing is carried out by a virus-coded protease and, in the absence of this enzyme activity, viral replication is blocked.
- derivatives linked to a heterocyclic group are potent inhibitors of retroviral proteases, both in a cell-free assay and in infected cells and, in addition, show antiviral activity in tissue culture assays. This activity renders such compounds useful for the
- retroviral infections in particular, those caused by HIV.
- R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl,
- R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 ) alkyl, aryl (C 1 -C 4 ) alkyl or heterocyclyl (C 1 -C 4 ) alkyl;
- R 3 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8
- cycloalkyl(C 1 -C 4 ) alkyl aryl(C 1 -C 4 ) alkyl, aryl(C 2 -C 4 )-alkenyl, heterocyclyl(C 1 -C 4 ) alkyl or heterocyclyl (C 2 -C 4 )-alkenyl;
- R 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl,
- each of R 5 , R 6 , R 7 and R 8 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; or R 5 and R 6 , or R 7 and R 8 may be joined together to form a 3 to 8 membered
- X is a 4-10 membered mono- or bicyclic
- heterocyclic group containing carbon ring atoms and one ring nitrogen atom through which the group is attached to the adjacent carbonyl group; the group may be saturated or partially unsaturated and, in addition to the -(CR 7 R 8 ) m -Het substituent, it may be substituted by up to 4 further substituents each independently chosen from F, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, OR 11 or NR 9 R 10 ;
- Het is an imidazolyl or triazolyl group either of which may optionally be substituted by C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, NR 9 R 10 or CONR 9 R 10 ,
- each of R 9 and R 10 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, or R 9 and R 10 may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen- containing heterocyclic group,
- R 11 is H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl
- n and m are each independently 0, 1 or 2;
- any alkyl or cycloalkyl group included in the aforementioned definitions may optionally be fully or partially substituted by fluorine.
- heterocyclyl means a 4 to 6 membered heterocyclic group containing as heteroatoms up to four nitrogen atoms, or an oxygen or sulphur atom optionally with one or two nitrogen atoms.
- the ring may be aromatic, or fully or partially saturated and may optionally be benzo-fused or substituted by C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkanoyl, C 1 -C 4 alkoxy, halo, hydroxy, oxo or aryl.
- Preferred heterocyclyl groups are pyridyl, pyrimidinyl, thienyl, isoquinolyl and tetrazolyl.
- aryl means phenyl optionally substituted with from 1 to 3 substituents each independently selected from C,-C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkoxy, C 2 -C 5 alkanoyl, hydroxy, halo, C 1 -C 4 alkyl fully or partially
- Halo means fluoro, chloro, bromo or iodo.
- the imidazolyl or triazolyl group, Het may be linked either by a ring carbon or ring nitrogen atom and may be unsubstituted or mono-, di or or tri-substituted.
- Triazolyl includes both 1,2,3 and 1,2,4-triazolyl groups.
- Alkyl and alkoxy groups containing 3 or more carbon atoms may be branched or straight-chain. Any alkyl, alkoxy or cycloalkyl group included in the above definitions may optionally be fully or partially substituted by fluorine.
- bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I).
- examples include ester derivatives formed between the free hydroxy group in the compound of formula (I) and, for example, an amino acid (such as L-valine).
- aryl is preferably phenyl and heterocyclyl is preferably oxetan-3-yl or 1,1-dioxothietan-3-yl.
- R 1 is preferably t-butyl
- R 1 isopropyl, oxetan-3-yl or 1,1-dioxothietan-3-yl and (CR 5 R 6 ) n is absent; or R 1 is phenyl and (CR 5 R 6 ) n is CH 2 ; or R 1 is H 2 NCO-, CH 3 NHCO- or (CH 3 ) 2 NCO- and (CR 5 R 6 ) n is CH 2 or CH(CH 3 ).
- Particularly preferred are compounds wherein R 1 is t-butyl, isopropyl or oxetan-3-yl and n is 0, most particularly where R 1 (CR 5 R 6 ) n - is t-butyl.
- aryl is preferably phenyl and heterocyclyl is for example pyridyl, pyrimidinyl or thienyl.
- R 2 is preferably aryl (C 1 -C 4 ) alkyl; benzyl is particularly preferred.
- aryl is preferably phenyl and heterocyclyl is preferably pyridyl, pyrimidinyl or thienyl.
- R 4 is preferably C 1 -C 6 alkyl; particularly preferred are isopropyl and sec-butyl (valine or isoleucine derivatives).
- the heterocyclic group X is preferably a 4-6 membered saturated or monounsaturated group and is most preferably an azetidine, pyrrolidine,
- piperidine tetrahydropyridine or piperidine group; piperidine being particularly preferred.
- R 7 and R 8 are preferably H and m is preferably O or 1.
- aryl is phenyl
- R 3 is preferably aryl (C 1 -C 4 ) alkyl or aryl (C 2 -C 4 ) alkenyl; R 3 is most preferably benzyl optionally substituted in the phenyl ring by fluoro, chloro, iodo, methyl, trifluoromethyl or trifluoromethoxy, or R 3 is 3-phenyl-prop-2-enyl or 3-phenylpropyl.
- Particular and preferred individual compounds include:
- bioprecursor therefor for use as a medicament, especially for use in the treatment or prophylaxis of human retroviral infections, in particular HIV
- the invention also includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt thereof or bioprecursor therefor, for the manufacture of a medicament for use in the
- the invention further includes a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, and a pharmaceutically
- the compounds of formula (I) are able to completely protect human T-cell line H9 for 7 days from the progressive effects of HIV infection.
- virus particles produced from virus-infected cells treated with a compound of formula (I) are non-infectious.
- infections which may be treated or prevented by the compounds of formula (I) include those caused by human or animal retroviruses, especially HIV-1.
- Clinical conditions which may therefore be treated or prevented include AIDS, ARC, and HIV related
- the compounds may also be used to block disease progression in symptomless infected
- Amide coupling reagents - e.g., 1-(3-dimethylaminopropyl)-3-ethyIcarbodiimide
- Protecting groups:- P; t-butoxycarbonyl or benzyloxy carbonyl are preferred
- X ' is either H or a protecting group, e.g., t-butyldimethylsilyl.
- Y is a group which is susceptible to nucleophilic displacement - succinimidooxy is preferred.
- the starting materials of formula (V) required for the procedure described above are in some cases
- N-t-butoxycarbonyl (BOC-) derivatives of the naturally occurring amino acids used in the synthesis of the compounds of the formula (VII) are commercially available as are their hydroxysuccinimido esters.
- the corresponding intermediates derived from unnatural amino acids can be prepared by standard procedures (see, for example, M. J. O'Donnell et al, J. Amer.
- the compounds of formula (II) can be prepared from the corresponding t-butyloxycarbonyl-protected amino-aldehydes (see D. H. Rich et al, J. Org. Chem., 1978, 43, 3624 and Y. Hamada et al, Chem. Pharm. Bull., 1982, 30(5), 1921)
- Amino protecting groups having varying levels of lability can be used. Such groups are known in the art and attention is directed to the reviews by Bodansky et al., "Peptide Synthesis", 2nd Ed., John Wiley & Sons, N.Y. (1976); Greene, “Protective Groups in Organic Synthesis”, John Wiley & Sons, N.Y. (1981); McOmie, “Protective Groups in Organic Chemistry", Plenum Press, N.Y. (1973); and to Sheppard in “Comprehensive Organic Chemistry, The Synthesis and Reactions of Organic
- amino-protecting groups include, but are not limited to, aminoxycarbonyl such as
- benzyloxycarbonyl substituted or unsubstituted aralkyl such as benzyl, trityl, benzhydryl and 4-nitrobenzyl; benzylidene; arylthio such as phenylthio, nitro-phenylthio and trichloro- phenylthio; phosphoryl derivatives such as dimethylphosphoryl and O,O-dibenzylphosphoryl; trialkylsilyl derivatives such as trimethylsilyl; and others as are described in U.S.
- the preferred amino protecting group for use in the above sequence is t-butoxycarbonyl.
- Procedures for substituting said group on a given amino group are well known. In general they comprise acylating the appropriate amino compound with the corresponding carbonyl chloride or anhydride in a reaction inert solvent, e.g. water, methylene chloride or tetrahydrofuran, in the presence of a base (acid acceptor) e.g., sodium or potassium hydroxide when water is solvent; and, when an organic solvent is used, in the presence of a tertiary amine such as a
- the pH of the reaction is typically held at about pH 8-10, and preferably at pH 9.
- the protected amino groups are converted to the unprotected amino groups by procedures known to those skilled in the art as appropriate to the particular group employed.
- the t-butoxycarbonyl group is, for example, readily removed by treatment with
- hydroxy-protecting groups are also known and are described in the literative sources already cited above.
- a preferred hydroxy protecting group is t-butyldimethylsilyl. This is introduced as previously described and is readily removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature.
- anhydrides and activated esters particularly those esters derived from N-hydroxyphthalimide, N-hydroxysuccinimide or 1-hydroxybenzotriazole, all of which are used in peptide syntheses.
- a dehydrative coupling agent is used to form the activated ester.
- Such coupling agents are 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide, N,N , dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, ethoxyacetylene, diphenylketene and N-ethyl-5-phenylisoxazoline-3'-sulfonate.
- the reaction conditions for using such coupling agents are well described in the literature. In general they comprise the use of a reaction inert solvent and temperatures ranging from ambient to 100°C.
- the above-mentioned carbodiimide reagents are favoured since they permit use of ambient reaction temperature and afford
- the invention includes a process for preparing a compound of the formula (I) which comprises removing the protecting group from a compound of the formula:
- X 1 is a selectively removable hydroxy-protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically
- the preferred protecting group for X 1 is t-butyldimethylsilyl; this is removed by treatment with tetra-n-butylammonium fluoride in an organic solvent, preferably tetrahydrofuran.
- Examples of pharmaceutically acceptable salts of the compounds (I) are acid-addition salts, e.g. sulfates, bisulfates, phosphates, lactates, mesylates, fumarates, citrates, succinates and gluconates.
- acid-addition salts e.g. sulfates, bisulfates, phosphates, lactates, mesylates, fumarates, citrates, succinates and gluconates.
- the compounds (I) will be administered by any suitable route, e.g. by the oral, parenteral (e.g. subcutaneous, intravenous,
- compositions which will contain an antiviral agent of the invention together with one or more of
- compositions can be prepared according to conventional techniques well known in pharmacy.
- Oral dosage forms include in particular syrups, tablets and capsules which may contain flavouring agents in
- Tablets can be made by conventional compression or moulding techniques by compressing a powder of the appropriate ingredients, e.g. the antiviral agent in conjunction with a binder, diluent, lubricant and surface-active agent.
- Rectal formulations will be in suppository form, and vaginal formulations as, for example, tampons, creams or foams.
- Parenteral formulations will be in sterile form, e.g. as vials for injection containing aqueous or non-aqueous diluents, buffers and antioxidants so that the formulation will be isotonic with blood.
- the appropriate dose of the anti-retroviral agents of the formula (I) will be from 1-50 mg/kg/day, preferably 1-25 mg/kg/day given in up to six divided doses per day. There may be of course instances where higher or lower dosages are merited according to the age, weight, degree of illness and response of the patient, and appropriate therapy will be as determined by the medical practitioner.
- the compounds of formula (I) may be used in combination with other drugs, some of which may be used.
- Such drugs include the following:-
- Reverse transcriptase inhibitors such as AZT, ddI, ddC, foscarnet, TIBO compounds, dipyrido- diazepinones or 6-substituted acyclopyrimidine (HEPT) derivatives;
- gp120-CD4 blockers such as dextran sulphate and soluble CD4, including its combination with toxic agents such as pseudomonas toxin;
- tat antagonists such as D-penicillamine
- interferons interleukins or colony stimulating factors, e.g. GM-CSF.
- the compounds of the invention were evaluated for antiviral activity by dissolving the test compound in 50 ⁇ l of DMSO and diluting in RPMI 1640, a complex salts solution with a pH of 7.2, to 1 mg/ml. Testing was performed at 0.001, 0.01, 0.1, 1 and 10 ⁇ g/ml against HIV 1 (strain IIIB) in a human T-cell line (H9). Untreated control infections were initiated at the same time.
- the compounds had an IC 100 values in the range 0.1 to 10.0 ⁇ g/ml.
- reaction mixture was stirred with hydrochloric acid (50 ml, 0.1N) for 15 minutes, ethyl acetate (50 ml) was then added and the resulting mixture stirred for 5 minutes.
- the organic layer was separated and the aqueous layer extracted with ethyl acetate (1 ⁇ 50 ml). The combined organic extracts were washed with
- N.M.R. (CDCI 3 ) ⁇ 1.15 (m, 2H); 1.45 (s, 9H); 1.58 (m, 2H); 1.85 (m, 1H); 2.65 (t, 2H); 3.80 (d, 2H); 4.10 (m, 2H); 6.90 (s, 1H); 7.10 (s, 1H); 7.45 (s, 1H).
- Oxetan-3-ol (2.0 g) and N,N-diisopropylethylamine (7.76 g) were dissolved in methylene chloride (50 ml) and the solution was added dropwise to a solution of bis-trichloromethyl carbonate (2.69 g) in methylene chloride (100 ml) maintained at -20 °C over a period of 15 minutes under an atmosphere of nitrogen.
- N.M.R. (DMSO-d 6 ) ⁇ 0.12(m,6H); 0.90 (m, 15H); 1.25- 1.29(2 x s,9H); 1.96(m,1H); 2.32-2.77 (m, 4H); 2.89(m,1H); 3.48-3.74 (m,2H); 3.88-4.06 (m, 3H) ; 4.18- 4.66(m,4H); 5.12(m,1H) ; 6.77(t,1H); 6.98(s,1H) ; 7.07- 7.32(m,10H); 7.40-7.82(2 x s,1H) ; 7.76-7.96(2 x s,1H);
- step (a) The product from step (a) (1.19 g) was dissolved in tetrahydrofuran and treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature. After 48 hours the solvent was removed under vacuum, the product taken up in ethyl acetate, washed with saturated aqueous sodium
- Example 1 The procedure of Example 1 was followed using 1- (N-t-butoxycarbonyl-(S)-valyl)-3(S)-imidazol-1-yl)pyrrolidine (Preparation 36) in the coupling step followed by removal of the t-butyldimethylsilyl group as described in Example 1(b) to give the title product. m.p. 111-112°C. Found: C, 61.90; H, 6.85; N, 9.61.
- the title compound was prepared from 1-(N-t-butoxycarbonyl-(S)-valyl-4-imidazol-1-ylpiperidine and (S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy-(R)-2-benzyl-6-phenylhexanoic acid using the same procedure as described in Example 1 step (a).
- N.M.R. (DMSO-d 6 ) ⁇ 0.12(m,6H); 0.91(m,15H); 1.13-1.30(m,2H); 1.26(s,9H); 1.47-1.76 (m, 2H); 1.89-2.08(m,4H); 2.36-2.97 (m, 6H); 3.50-3.75 (m, 2H); 3.99-4.61(m,4H); 6.79(m,1H); 6.90(d,1H); 7.07-7.29 (m, 11H); 7.68-7.73(2 x s,1H); 7.93-7.99(2 x d,1H).
- the benzyloxycarbonyl protecting group was removed from 1-(N-benzyloxycarbonyl)-4-(1,2,4-triazol-4-yl)-piperidine (Preparation 32) by catalytic hydrogenation and the resulting amine product coupled to N-((R)-2-benzyl-(S)-5-t-butoxycarbonylamino-(S)-4-t-butyldimethylsilyloxy)-6-phenylhexanoyl)-(S)-valine following the procedure described for Example 1 step (a), to give 1-[N-((R)-2-benzyl-(S)-5-(t-butoxycarbonylamino)-(S)-4-(t-butyldimethylsilyloxy)-6-phenylhexanoyl)-(S)-valyl]-4-(1,2,4-triazol-4-yl)piperidine, m/e 761 (MH + ) .
- Example 1(b) gave the title product, free base. This was dissolved in absolute ethanol and treated with a solution of 1-tartaric acid (0.14 g) in absolute ethanol. Addition of ether gave a precipitate which was filtered and dried to give the 1-tartrate salt as a colourless solid, m.p. 92-152°C (0.61 g). Found: C,
- step c) The product from step b) above (404 mg) and 1-isocyano-3-methyl-1-(p-toluenesulphonyl)-but-1-ene, (from Preparation 51, 150 mg) were stirred together in methanol (15 ml) with diisopropylethylamme (100 mg) for 16 hours.
- Example 16 The product from Example 16 (4.0 g) was dissolved in methylene chloride (40 ml) and cooled in an ice bath. Trifluoroacetic acid (10 ml) was added dropwise over a period of 5 minutes and the solution stirred at 0°C for 1.5 hours. The solvent was evaporated under vacuum and the residue taken up in ethyl acetate (250 ml) and washed with 1M sodium hydroxide (50 ml) and brine (50 ml). The organic solution was dried (MgSO 4 ), filtered and the solvent was evaporated under vacuum.
- step b) The product from step a) (0.818 g) was dissolved in methylene chloride (30 ml). 3-Oxetanylcarbonyloxy-succinimide (0.344 g) was added and the solution stirred at room temperature for one hour. The solution was then washed with 0.5M sodium hydroxide (15 ml) and brine (15 ml), dried (MgSO 4 ), filtered and evaporated under vacuum. The resulting solid was recrystallised from ethyl acetate to give the title compound as a white solid, m.p. 201-203 °C. Found: C,60.32; H,6.22;
- dicyclohexylcarbodiimide (0.51 g) were dissolved in dichloromethane (25 ml) and the mixture was stirred for 3 hours. The precipitated dicyclohexylurea was removed by filtration and the filtrate evaporated to a white foam. This white foam was commoned with the product of Example 16 in N,N-dimethylformamide (20 ml) and 4-dimethylaminopyridine (0.025 g. added. After stirring at room temperature fcr five days the fixture was partitioned between ethyl acetate and water.
- step b) The product from step a) above (0.95 g) was dissolved in absolute ethanol (50 ml), and the solution was treated with 10% palladium on charcoal (0.1 g) and hydrogenated at 60p.s.i., (4.1 bar) at room temperature for 4 hours. After removal of the catalyst the filtrate was evaporated to dryness. Purification by silica-gel chromatography eluting with dichloromethane-methanol-concentrated aqueous ammonia (97:3:0.5) gave the product as a white foam. This foam was dissolved in ethyl acetate (6 ml) and a solution of tartaric acid (0.089 g) in 10% methanol ethyl acetate (10 ml) was added. Evaporation of the solvent and trituration with diethyl ether gave the product as a white glass (0.48 g), m.p. 122°C. Found C, 56.74; H, 6.78; N, 8.56.
- N.M.R. (DMSO-d 6 ) ⁇ 0.8-0.95 (m, 12H); 1.2 (s, 11H); 1.35-1.77 (m, 2H); 1.8-2.15 (m, 4H); 2.4-3.2 (m, 8H); 3.51 (m, 1H); 3.8 (m, 1H); 4.1 (m, 1H); 4.3 (m, 1H); 4.4-4.65 (m, 2H); 4.81 (m, 1H); 6.83 (s, 1H); 7.0-7.32 (m, 12H); 7.66 (d, 1H); 7.73-8.0 (m, 1H).
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
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- Communicable Diseases (AREA)
- Oncology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5516236A JPH07501556A (en) | 1992-03-25 | 1993-03-13 | antiviral peptide |
EP93906535A EP0632808A1 (en) | 1992-03-25 | 1993-03-13 | Antiviral peptides |
SK1140-94A SK114094A3 (en) | 1992-03-25 | 1993-03-13 | Peptides, method of their producing, their using and pharmaceutical preparation on their base |
BR9306138A BR9306138A (en) | 1992-03-25 | 1993-03-13 | Antiviral Peptides |
FI944428A FI944428A0 (en) | 1992-03-25 | 1994-09-23 | Antiviral peptides |
NO943540A NO943540L (en) | 1992-03-25 | 1994-09-23 | Antiviral peptides |
KR1019940703314A KR950700901A (en) | 1992-03-25 | 1994-09-24 | Antiviral peptides (ANTIVIRAL PEPTIDES) |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929206462A GB9206462D0 (en) | 1992-03-25 | 1992-03-25 | Antiviral peptides |
GB9206462.5 | 1992-03-25 | ||
GB9301638.4 | 1993-01-27 | ||
GB939301638A GB9301638D0 (en) | 1993-01-27 | 1993-01-27 | Antiviral peptides |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993019059A1 true WO1993019059A1 (en) | 1993-09-30 |
Family
ID=26300586
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/000597 WO1993019059A1 (en) | 1992-03-25 | 1993-03-13 | Antiviral peptides |
Country Status (13)
Country | Link |
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EP (1) | EP0632808A1 (en) |
JP (1) | JPH07501556A (en) |
KR (1) | KR950700901A (en) |
AU (1) | AU3748393A (en) |
BR (1) | BR9306138A (en) |
CA (1) | CA2131154A1 (en) |
CZ (1) | CZ229594A3 (en) |
FI (1) | FI944428A0 (en) |
HU (1) | HU9402744D0 (en) |
NO (1) | NO943540L (en) |
RU (1) | RU94041225A (en) |
SK (1) | SK114094A3 (en) |
WO (1) | WO1993019059A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0790248A1 (en) | 1996-01-27 | 1997-08-20 | Pfizer Limited | 3-Aza-piperidone- (tetrahydropyrimidin-2-one) and 3-oxa-piperidone (1,3 oxazin-2-one) derivatives, their preparation and their use as tachykinin/neurokinin antagonists |
US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
WO1999038862A1 (en) * | 1998-02-02 | 1999-08-05 | Lg Chemical Ltd. | Farnesyl transferase inhibitors having a piperidine structure and process for preparation thereof |
US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US6809200B2 (en) | 2000-07-28 | 2004-10-26 | Pfizer Inc. | Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990003971A1 (en) * | 1988-10-04 | 1990-04-19 | Abbott Laboratories | Non-peptide renin inhibitors |
EP0365992A1 (en) * | 1988-10-19 | 1990-05-02 | Abbott Laboratories | Heterocyclic peptide renin inhibitors |
EP0386611A2 (en) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
WO1990012804A2 (en) * | 1989-04-18 | 1990-11-01 | The Upjohn Company | Peptides having novel polar n-terminal groups |
EP0437729A2 (en) * | 1990-01-18 | 1991-07-24 | Bayer Ag | New peptides, procedure for their preparation and their use as a medicament, especially their use as medicament against retroviruses |
-
1993
- 1993-03-13 SK SK1140-94A patent/SK114094A3/en unknown
- 1993-03-13 AU AU37483/93A patent/AU3748393A/en not_active Abandoned
- 1993-03-13 HU HU9402744A patent/HU9402744D0/en unknown
- 1993-03-13 EP EP93906535A patent/EP0632808A1/en not_active Withdrawn
- 1993-03-13 JP JP5516236A patent/JPH07501556A/en active Pending
- 1993-03-13 CA CA002131154A patent/CA2131154A1/en not_active Abandoned
- 1993-03-13 CZ CZ942295A patent/CZ229594A3/en unknown
- 1993-03-13 RU RU94041225/04A patent/RU94041225A/en unknown
- 1993-03-13 BR BR9306138A patent/BR9306138A/en not_active Application Discontinuation
- 1993-03-13 WO PCT/EP1993/000597 patent/WO1993019059A1/en not_active Application Discontinuation
-
1994
- 1994-09-23 NO NO943540A patent/NO943540L/en unknown
- 1994-09-23 FI FI944428A patent/FI944428A0/en unknown
- 1994-09-24 KR KR1019940703314A patent/KR950700901A/en not_active Ceased
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990003971A1 (en) * | 1988-10-04 | 1990-04-19 | Abbott Laboratories | Non-peptide renin inhibitors |
EP0365992A1 (en) * | 1988-10-19 | 1990-05-02 | Abbott Laboratories | Heterocyclic peptide renin inhibitors |
EP0386611A2 (en) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
WO1990012804A2 (en) * | 1989-04-18 | 1990-11-01 | The Upjohn Company | Peptides having novel polar n-terminal groups |
EP0437729A2 (en) * | 1990-01-18 | 1991-07-24 | Bayer Ag | New peptides, procedure for their preparation and their use as a medicament, especially their use as medicament against retroviruses |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5716973A (en) * | 1991-01-02 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Anti-viral compounds |
US5717093A (en) * | 1993-07-08 | 1998-02-10 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US5831094A (en) * | 1993-09-09 | 1998-11-03 | Merrell Pharamceuticals Inc. | Difluoro statone antiviral analogs |
US5948778A (en) * | 1993-09-09 | 1999-09-07 | Merrel Pharmaceuticals Inc. | Difluoro statone antiviral analogs |
US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
EP0790248A1 (en) | 1996-01-27 | 1997-08-20 | Pfizer Limited | 3-Aza-piperidone- (tetrahydropyrimidin-2-one) and 3-oxa-piperidone (1,3 oxazin-2-one) derivatives, their preparation and their use as tachykinin/neurokinin antagonists |
WO1999038862A1 (en) * | 1998-02-02 | 1999-08-05 | Lg Chemical Ltd. | Farnesyl transferase inhibitors having a piperidine structure and process for preparation thereof |
US6809200B2 (en) | 2000-07-28 | 2004-10-26 | Pfizer Inc. | Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-one compounds and intermediates thereof |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
Also Published As
Publication number | Publication date |
---|---|
KR950700901A (en) | 1995-02-20 |
NO943540L (en) | 1994-11-21 |
AU3748393A (en) | 1993-10-21 |
RU94041225A (en) | 1996-07-20 |
BR9306138A (en) | 1998-06-23 |
FI944428A7 (en) | 1994-09-23 |
CZ229594A3 (en) | 1995-04-12 |
FI944428A0 (en) | 1994-09-23 |
CA2131154A1 (en) | 1993-09-30 |
EP0632808A1 (en) | 1995-01-11 |
JPH07501556A (en) | 1995-02-16 |
NO943540D0 (en) | 1994-09-23 |
SK114094A3 (en) | 1995-04-12 |
HU9402744D0 (en) | 1994-12-28 |
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