WO1993023373A1 - HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX - Google Patents
HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX Download PDFInfo
- Publication number
- WO1993023373A1 WO1993023373A1 PCT/EP1993/000592 EP9300592W WO9323373A1 WO 1993023373 A1 WO1993023373 A1 WO 1993023373A1 EP 9300592 W EP9300592 W EP 9300592W WO 9323373 A1 WO9323373 A1 WO 9323373A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- product
- cycloalkyl
- hydroxy
- dmso
- Prior art date
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- 239000003443 antiviral agent Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 35
- 125000003118 aryl group Chemical group 0.000 claims abstract description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 24
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 238000011282 treatment Methods 0.000 claims abstract description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 206010038997 Retroviral infections Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 238000011321 prophylaxis Methods 0.000 claims abstract description 6
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 3
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims abstract description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 141
- -1 phenoxy, phenylsulphonyl Chemical group 0.000 claims description 94
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 46
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 208000015181 infectious disease Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 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 2
- 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 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- IOQWYHVOUPBBGC-RKKBZCJMSA-N tert-butyl N-[(2R,3S,5S)-5-benzyl-6-[[(1S)-1-cyclohexyl-2-[4-(2-methoxyethylamino)piperidin-1-yl]-2-oxoethyl]amino]-3-hydroxy-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound C(C1=CC=CC=C1)[C@H](C(=O)N[C@H](C(=O)N1CCC(CC1)NCCOC)C1CCCCC1)C[C@@H]([C@@H](CC1=CC=CC=C1)NC(=O)OC(C)(C)C)O IOQWYHVOUPBBGC-RKKBZCJMSA-N 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 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
- 229910052799 carbon Inorganic materials 0.000 abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 337
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 218
- 239000000047 product Substances 0.000 description 199
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 239000000243 solution Substances 0.000 description 108
- 239000000543 intermediate Substances 0.000 description 87
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 84
- 238000002360 preparation method Methods 0.000 description 71
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- 229910001868 water Inorganic materials 0.000 description 54
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 44
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 42
- 239000002904 solvent Substances 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 229960001866 silicon dioxide Drugs 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- 239000006260 foam Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 235000017557 sodium bicarbonate Nutrition 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000001704 evaporation Methods 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 150000002596 lactones Chemical class 0.000 description 13
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 241000725303 Human immunodeficiency virus Species 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 230000029936 alkylation Effects 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000000284 extract Substances 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 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 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 238000006268 reductive amination reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 3
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 3
- 206010001513 AIDS related complex Diseases 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 3
- 150000001261 hydroxy acids Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 2
- UEVGWVOLUCPPDE-ZNZIZOMTSA-N (2r,4s,5s)-2-benzyl-4-[tert-butyl(dimethyl)silyl]oxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]-6-phenylhexanoic acid Chemical compound C([C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](CC=1C=CC=CC=1)C(O)=O)O[Si](C)(C)C(C)(C)C)C1=CC=CC=C1 UEVGWVOLUCPPDE-ZNZIZOMTSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
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- FXEYGOYVUJFORB-UHFFFAOYSA-N tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate Chemical compound CNCC1CCN(C(=O)OC(C)(C)C)CC1 FXEYGOYVUJFORB-UHFFFAOYSA-N 0.000 description 1
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- XTCCOVXYCWMKFE-DEGSFCBCSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-3-methyl-1-[4-(methylamino)piperidin-1-yl]-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[[4-(trifluoromethoxy)phenyl]methyl]hexan-2-yl]carbamate Chemical compound C1CC(NC)CCN1C(=O)[C@H](C(C)C)NC(=O)[C@H](CC=1C=CC(OC(F)(F)F)=CC=1)C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 XTCCOVXYCWMKFE-DEGSFCBCSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 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
- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- 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
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- 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
- C07D405/02—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 two hetero rings
- C07D405/10—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 two hetero rings linked by a carbon chain containing aromatic rings
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- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- 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
Definitions
- the present invention relates to certain peptide derivatives containing a heterocyclic group which are useful in the treatment or prophylaxis of human retroviral infections.
- HIV human immunodeficiency virus
- Infection with HIV is characterised by progressive breakdown of the immune system and CNS dysfunction. Severely immune deficient patients suffer from a wide range of opportunistic infections (e.g. pneuroocvstis carinii, human cyteimegalovirus, or Candida), and cancers such as Kaposi's sarcoma. Loss of cells, particularly
- CD4 + lymphocytes following infection with HIV is an important factor in the progressive impairment of immune function.
- the infection of cells of raor ⁇ x-yte/macrophage lineage with HIV also contributes to the observed pathology. Unas, 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.
- 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 treatment and prophylaxis of retroviral infections, in particular, those caused by HIV.
- the invention provides cxfmp ⁇ unds of the formula:-
- R 1 is C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, aryl, heterocyclyl or R 7 R 8 NCO;
- 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, aryl or heterocyclyl;
- R 5 and R 6 are each independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl substituted by C 1 -C 4 alkoxy, hydroxy or NR 7 R 8 ; or R 5 and R 6 are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-(C 1 -C 4 alkyl)piperazine group;
- each of R 7 and R 8 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl or R 7 and R 8 may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen-containing heterocyclic group; each of R 9 , R 10 , R 11 and R 12 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, or R 6 and R 10 , or R 11 and R 12 may be joined together to form a 3 to 8 membered carbocyclic ring;
- 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 11 R 12 ) -NR 5 R 6 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, OH, C 1 -C 6 alkoxy or NR 7 R 8 ;
- 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 1 -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 1 -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 substituted by fluorine, C 1 -C 4 alkoxy fully or partially substituted by fluorine, phenyl, phenoxy, benzyl, benzoyl, phenylSO 2 -, pyridyl, tetrazolyl, phenyltetrazolyl, NR 7 R 8 or
- Halo means fluoro, chloro, bromo or iodo.
- 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 corpound 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, isopropyl, oxetan-3-yl or 1,1-dioxothietan-3-yl and (CR 9 R 10 ) is absent; or R 1 is phenyl and
- n is CH 2 ; or R 1 is H 2 NCO-, CH 3 NHCO- or (CH 3 ) 2 NCO- and
- (CR 9 R 10 ) 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 9 R 10 ) - 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 mor-ounsaturated group and is most preferably an azetidine, pyrrolidine, tetrahydropyridine or piperidine group; piperidine being particularly preferred.
- R 7 and R 8 are preferably H and m is preferably 0 or 1.
- aryl is phenyl, unsubstituted or substituted as defined in the term aryl above, and heterocyclyl is for example pyridyl, pyrimidinyl, lsoquinolyl or thienyl.
- 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 methyl, chloro, trifluoromethyl, trifluoromethoxy, pivaloyl, OH,
- CONMe 2 phenoxy, phenylsulphonyl or pyridyl or is 3-phenylpropyl or 3-phenyl-prop-2-enyl.
- Particular and preferred individual compounds include:
- a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament, especially for use in the treatment or prophylaxis of human retroviral
- the invention also includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prophylaxis or treatment of retroviral infections.
- the invention further includes a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
- the antiviral activity of the compounds of general formula (I) is established using in vitro assay systems.
- the co ⁇ rpounds of formula (I) are able to completely protect human T-cell line H9 for 7 days from the progressive effects of HIV infection.
- Untreated virus-infected cells display typical cytopathic effects such as formation of syncytia and cell death, m addition, virus particles produced from virus-infected cells treated with a compound of formula (I) are non-infectious.
- infections which may be treated or prevented fcy the compounds of formula (I) include those caused by human or animal refcroviruses, especially EHV-1.
- Clinical conditions which may therefore be treated or prevented include AIDS, ARC, and HEV related dementia.
- the compounds may also be used to block disease progression in symptomless infected individuals.
- the compounds of formula (I) can be prepared using the coupling and protection techniques which are familiar to those skilled in the art of peptide chemistry.
- 4-ketopiperidine group is carried through to the coupling stage and the reductive animation conducted on the coupled, protected product (XII) to give the product (IX) which is then deprotected to give the final product as before.
- the process can be performed with the appropriate group present in the starting material of formula (II), or it can be performed using a coitpound of formula (IV) wherein R 1 is t-butyl (BOC derivative), and this is then removed after coupling to the intermediate (VIII) for exairple by treatment with trifluoroacetic acid.
- the free amine is then reacylated, for exairple, in the case where R 1 is oxetanyl and n is O, by reaction with 3-oxetanyloxycarbonyloxysuccinimide, before final removal of the protecting groups.
- the above sequences can be adapted as appropriate to be performed with any of the variants claimed for R 1 to R 12 by appropriate selection of starting materials.
- amino-protecting groups include but are not limited to aryloxycarbonyl such as benzyloxycarbonyl; substituted or unsubstituted aralkyl such as benzyl, trityl, benzhydryl and 4-nitrobenzyl; benzylidene;
- arylthio such as phenylthio, nitrqphenylthio and trichlorophenylthio
- phosphoryl derivatives such as dimethylphosphoryl and O,O-dibenzylphosphoryl
- trialkylsilyl derivatives such as trimethylsilyl
- 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 triethylamine or pyridine.
- a reaction inert solvent e.g. water, methylene chloride or tetrahydrofuran
- a base e.g., sodium or potassium hydroxide when water is solvent
- a tertiary amine such as a triethylamine or pyridine.
- pH of the reaction is typically held at about pH 8-10
- 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 exairple, readily removed by treatment with dichloromethane saturated with hydrogen chloride gas.
- 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.
- esters derived from N-hydroxyphtoalimide, N-hydroxysuccinimide or 1-hydroxybenzotriazole are used in peptide syntheses.
- a dehydrative coupling agent is used to form the activated ester.
- Such coupling agents are 1-cyclohexyl-3-(2-morpholincethyl)carbodiimide, N,N'dicyclohejylcarbodiimide, N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, ethoxyacetylene, diphenylketene and N-ethyl-5-phenyl-isoxazoliner-3'-sulfonate.
- the reaction conditions for using such coupling agents are well described in the literature.
- the various protecting groups can be removed by the appropriate techniques previously discussed, and the compounds of the formula (I) isolated and purified using conventional procedures such as recrystallisation or column dircimatography.
- N-t-butoxycarbonyl (BOC-) derivatives of the naturally occurring amino acids used in the synthesis of the compounds of the formula (V) are commercially available as are their
- hvdroxysuccinimido esters The corresponding intermediates derived from unnatural amino acids can be prepared by standard procedures (see, for exairple, M. J. O'Donnell et. al., J. Amer. Chem. Soc., 1989, 111, 2353).
- the co ⁇ p ⁇ unds 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) by reaction with ethyl propiolate (see A. H. Fray et. al., J. Org. Chem., 1986, 51, 4828), followed by reduction to give the
- Compounds of formula (XIII) can be prepared by conventional synthetic methods, for example by coupling a N-protected amino acid with a N-substituted or N-protected 4-aminomethyl piperidine derivative.
- the invention includes a process for preparing a compound of the formula (I) which comprises removing the protecting groups from a compound of the formula:
- X 1 is either H or a selectively removable hydroxy- protecting group and Y 1 is either R 6 , or a selectively removable nitrogen-protecting group and R 1 to R 6 are as previously defined with the proviso that at least one of X 1 and Y 1 is a protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.
- the preferred protecting group for X is t-butyldimethylsilyl; this is removed by treatment with tetra-n-butylammonium fluoride in an organic solvent, preferably tetrahydrofuran.
- the preferred protecting group for Y is benzyloxycarbonyl; this is removed by catalytic hydrogenation.
- novel intermediates of formulae (IX) , (XI) , (XII) and (XIV) also form part of this invention.
- Examples of pharmaceutically acceptable salts of the ccarpounds (I) are acid-addition salts, e.g. sulfates, bisulfates, phosphates, acetates, lactates, maleates, mesylates, fumarates, citrates, succinates and gluconates.
- acid-addition salts e.g. sulfates, bisulfates, phosphates, acetates, lactates, maleates, 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, int ramuscular, or intradermal) , rectal, nasal, topical (including buccal and sublingual) or vaginal routes.
- parenteral e.g. subcutaneous, intravenous, int ramuscular, or intradermal
- nasal including buccal and sublingual
- vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal)
- nasal, topical (including buccal and sublingual) or vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal)
- nasal including buccal and sublingual
- vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intra
- Rectal formulations will be in suppository form, and vaginal formulations as, for example, tampons, creams or foams.
- formulations will be in sterile form, e.g. as vials for injection containing aqueous or non-aqueous diluents, buffers and
- 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 c ompounds of formula (I) may be used in combination with other drugs, same of which may potentiate their activity.
- drugs include the following:- (a) Reverse transcriptase inhibitors such as AZT, ddI, ddC, foscarnet, TIBO compounds, dipyridodiazepinones or
- gp120-CD4 blockers such as dextran sulphate and soluble CD4, including its combination with toxic agents such as
- interleukins or colony sti-mulating 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 REMI 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 as ⁇ g/ml against HIV 1 (strain IIIB) in a human T-cell line (H9) . Untreated control infections were initiated at the same time.
- tissue culture supernatants were titrated for the presence of infectious virus on C8166 cells (human T-cell line).
- C8166 cells human T-cell line
- 5 and 7 cultures were examined for appearance of syncytia.
- Control infections, untreated with drug, show typical viral cytopathic effects, including formation of syncytia and cell death.
- the IC 100 quoted is the lowest test concentration affording coirplete protection to the culture. Using this test method, the compounds had an IC 100 values in the range 0.1 to 10.0 ⁇ g/ml.
- intermediate (3b) by reductive amination of intermediate (3a) with metiiylamine.
- sucoinimide esters were prepared from the appropriate alcohol using the method described above.
- N,N- dimethylformamide (5 ml) was added to an active ester solution previously prepared by stirring together the product from
- Example 3 The product from Example 3 (1.75 g) in tetrahydrofuran (150 ml) was treated with 1M tetra-n-butylammonium fluoride in
- Example 7 The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 6 with ammonium acetate, m.p.161°. Found: C,68.32; N,8.59; N,9.03.
- Example 1 by reacting the amine derived from 1-(N-t-butoxycarbonyl)-(S)-valyl-4-(pyrrolidin-1-yl)piperidine with an active ester derived from the product from intermediate
- the title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 12 with an active ester derived from the product from intermediate preparation (2b).
- N.M.R. (DMSO-d 6 ) ⁇ 0.8(m,6H); 1.0(t,3H); 1.35(s,9H); 1.4-1.8(m,4H); 1.9(m,1H); 2.5(m,2H); 3.0-3.2 (m,2H); 3.9-4.3 (m,3H); 4.5(m,1H); 5.1(s,2H); 6.7 & 6.9(2x d,1H); 7.4(m,5H).
- the title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 17 with an active ester derived from the product from intermediate preparation (2b).
- Example 7 by reacting the product from Example 23 with methylamine.
- the title compound was prepared from the product from Example 24 by the same procedure as described for Example 2, m.p. 149-151°.
- the title compound was prepared from the product from Example 42 by the same procedure as described for Example 2, m.p. 145-147° .
- CH 2 Cl 2 requires C,68.36; H,9.18; N,7.05%.
- a solution of the product from Example 47 (45 g) in acetic acid (300 ml) was treated with platinum oxide (0.5 g) and was stirred under an atmosphere of hydrogen at 60 psi (4.1 bar) and 60°C for 24 hours before the solvent was removed by evaporation under vacuum.
- a solution of the residue in methylene chloride (300 ml) was treated at room teiiperature with di-tert-butyl dicarbonate (50.2 g) and stirred for a further 18 hours.
- N-t-butoxycarbonyl valine (1.91 g) , 1-hydroxybenzotriazole hydrate (1.31 g) , 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g) and N,N-diisopropylethylamine (7.7 ml) in methylene chloride (100 ml) for 30 minutes was treated with the product from
- N.M.R. (DMSO-d 6 ) 5 0.8(m,6H) ; 1.0(m,2H) ; 1.35(s,9H) ; 1.65(m,3H) ; 1.9 (m,1H) ; 2.5(m,1H) ; 2.85-3.05 (m, 3H) ; 4.0(m,1H) ; 4.2 (m,1H) ;
- Example 58 The title compound was prepared from the product of Example 58 by the same procedure as described for Example 49.
- Example 59 The title compound was prepared from the product of Example 59 by the same procedure as described for Example 50. Purification fcy chromatography on silica-gel, eluting with hexane-ethyl acetate (3:2) gave the title compound as a colourless oil.
- the title ccatpound was prepared from the product of Example 60 by the same procedure as described for Example 51, m.p. 193-196°.
- N.M.R. (DMSO-d 6 ) ⁇ 0.1(s,6H); 0.8(m,6H); 0.9(s,9H); 0.95-1.25(m,3H); 1.3(s,9H); 1.6(m,2H); 1.75(m,3H); 1.95(m,1H); 2.4-2.95-3.1(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45-3.7 (m,2H) ; 3.9 (m,1H) ; 4.15 (m, 1H) ; 4.55 (m,1H) ; 6.75 (m,1H) ; 7.05-7.35 (m, 9H) ; 7.95 & 8.05 (2xd,1H) .
- N.M.R. (EMSO-d 6 ) ⁇ 0.75(m,6H); 1.0(m,4H); 1.3(s,9H); 1.2-1.8(m,5H); 2.5-3.05(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45(m,1H); 3.55(m,1H); 3.8(m,1H); 4.1(m,1H); 4.55(m,2H); 6.4(m,1H); 7.0-7.25(m,9H); 7.85(m,1H).
- Example 79 The title compound was prepared from the product of Example 79 and the product from Intermediate Preparation (4b) by the same procedure as described for Example 3, m.p. 80-90° (glass) .
- Example 80 The title compound was prepared from the product of Example 80 by the same procedure as described for Example 4, m.p. 188-190°.
- N.M.R. (DMSO-d 6 ) ⁇ 0.8-1.4 (m,8H) ; 1.3 (s,9H) ; 1.4-1.85 (m,9H) ; 2.4-3.1(m,10H) ; 3.2(s,3H) ; 3.35(t,2H) ; 3.45(m,1H) ; 3.55(m,1H) ; 3.85(m,1H) ; 4.1(m,1H) ; 4.55(m,2H) ; 6.4(d,1H) ; 7.2 (m,10H) ;
- the title compound was prepared from the product from Example 95 by the procedure as described for Example 73.
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5519802A JPH07503482A (ja) | 1992-05-20 | 1993-03-13 | N−〔N’−(5−アミノ−4−ヒドロキシ−アシロイル)−α−アミノアシロイル〕置換された複素環式化合物および抗ウイルス物質としての使用 |
EP93906530A EP0641319A1 (fr) | 1992-05-20 | 1993-03-13 | HETEROCYCLES A SUBSTITUTION N- N'-(5-AMINO-4-HYDROXY-ACYLOYL)-$g(a)-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX |
FI945438A FI945438A0 (fi) | 1992-05-20 | 1994-11-18 | N-/N'-(5-amino-4-hydroksiasyloyyli)-alfa aminoasyloyyli/substituoidut heterosyklit ja niiden käyttö antiviraalisina aineina |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9210744.0 | 1992-05-20 | ||
GB929210744A GB9210744D0 (en) | 1992-05-20 | 1992-05-20 | Antiviral peptides |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993023373A1 true WO1993023373A1 (fr) | 1993-11-25 |
Family
ID=10715780
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/000592 WO1993023373A1 (fr) | 1992-05-20 | 1993-03-13 | HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0641319A1 (fr) |
JP (1) | JPH07503482A (fr) |
AU (1) | AU3748293A (fr) |
CA (1) | CA2133583A1 (fr) |
FI (1) | FI945438A0 (fr) |
GB (1) | GB9210744D0 (fr) |
WO (1) | WO1993023373A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5538997A (en) * | 1993-03-12 | 1996-07-23 | Sandoz Ltd. | 2,4-diamino-3-hydroxycarboxylic acid derivatives |
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 |
US6114380A (en) * | 1995-12-18 | 2000-09-05 | Merrell Pharmaceuticals Inc. | Difluoro statone analogs |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2850377B1 (fr) * | 2003-01-23 | 2009-02-20 | Sanofi Synthelabo | Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0312157A2 (fr) * | 1987-10-13 | 1989-04-19 | Merck & Co. Inc. | Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux |
EP0386611A2 (fr) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Dérivés d'acides aminés |
-
1992
- 1992-05-20 GB GB929210744A patent/GB9210744D0/en active Pending
-
1993
- 1993-03-13 WO PCT/EP1993/000592 patent/WO1993023373A1/fr not_active Application Discontinuation
- 1993-03-13 EP EP93906530A patent/EP0641319A1/fr not_active Withdrawn
- 1993-03-13 JP JP5519802A patent/JPH07503482A/ja active Pending
- 1993-03-13 CA CA002133583A patent/CA2133583A1/fr not_active Abandoned
- 1993-03-13 AU AU37482/93A patent/AU3748293A/en not_active Abandoned
-
1994
- 1994-11-18 FI FI945438A patent/FI945438A0/fi not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0312157A2 (fr) * | 1987-10-13 | 1989-04-19 | Merck & Co. Inc. | Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux |
EP0386611A2 (fr) * | 1989-03-06 | 1990-09-12 | F. Hoffmann-La Roche Ag | Dérivés d'acides aminés |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5538997A (en) * | 1993-03-12 | 1996-07-23 | Sandoz Ltd. | 2,4-diamino-3-hydroxycarboxylic acid derivatives |
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 |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
Also Published As
Publication number | Publication date |
---|---|
CA2133583A1 (fr) | 1993-11-25 |
GB9210744D0 (en) | 1992-07-08 |
FI945438A (fi) | 1994-11-18 |
EP0641319A1 (fr) | 1995-03-08 |
JPH07503482A (ja) | 1995-04-13 |
FI945438A0 (fi) | 1994-11-18 |
AU3748293A (en) | 1993-12-13 |
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