WO1998045298A1 - Antiviral agents - Google Patents
Antiviral agents Download PDFInfo
- Publication number
- WO1998045298A1 WO1998045298A1 PCT/GB1998/001021 GB9801021W WO9845298A1 WO 1998045298 A1 WO1998045298 A1 WO 1998045298A1 GB 9801021 W GB9801021 W GB 9801021W WO 9845298 A1 WO9845298 A1 WO 9845298A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- oxazin
- thieno
- substituted
- hydrogen
- Prior art date
Links
- 239000003443 antiviral agent Substances 0.000 title description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 241001529453 unidentified herpesvirus Species 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 7
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- -1 polymethylene Polymers 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- JYQQWQJCEUMXQZ-UHFFFAOYSA-N methyl cyanate Chemical compound COC#N JYQQWQJCEUMXQZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- ZPZIFQIXCDWUFN-UHFFFAOYSA-N thieno[3,2-d][1,3]oxazin-4-one Chemical compound O=C1OC=NC2=C1SC=C2 ZPZIFQIXCDWUFN-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- SFDGJDBLYNJMFI-UHFFFAOYSA-N 3,1-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)OC=NC2=C1 SFDGJDBLYNJMFI-UHFFFAOYSA-N 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- HEWJTWBYNJRJJL-UHFFFAOYSA-N thieno[2,3-d][1,3]oxazin-4-one Chemical class O=C1OC=NC2=C1C=CS2 HEWJTWBYNJRJJL-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 108091005804 Peptidases Proteins 0.000 description 14
- 239000004365 Protease Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000007792 addition Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 102000035195 Peptidases Human genes 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CFIYJBCXTZGBIL-UHFFFAOYSA-N 2-[4-(3-nitrobenzoyl)phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C(=O)C1=CC=CC([N+]([O-])=O)=C1 CFIYJBCXTZGBIL-UHFFFAOYSA-N 0.000 description 2
- OQIFTAJMGYVKGG-UHFFFAOYSA-N 2-amino-4-methylthiophene-3-carboxylic acid Chemical compound CC1=CSC(N)=C1C(O)=O OQIFTAJMGYVKGG-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 2
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical group O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 108010085189 HSV-2 protease Proteins 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
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- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- UURQMGIRHYSQKX-UHFFFAOYSA-N methyl 2-[4-(3-nitrobenzoyl)phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C(=O)C1=CC=CC([N+]([O-])=O)=C1 UURQMGIRHYSQKX-UHFFFAOYSA-N 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FJSHTWVDFAUNCO-UHFFFAOYSA-N 2-(4-iodophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(I)C=C1 FJSHTWVDFAUNCO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- VYNRDZHHFONHMH-UHFFFAOYSA-N 2-amino-4,5-dimethylthiophene-3-carboxylic acid Chemical compound CC=1SC(N)=C(C(O)=O)C=1C VYNRDZHHFONHMH-UHFFFAOYSA-N 0.000 description 1
- MCDXWLAYOXBQBG-UHFFFAOYSA-N 2-amino-4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2CC(=O)N(N)OC2=C1 MCDXWLAYOXBQBG-UHFFFAOYSA-N 0.000 description 1
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 101150060044 UL26 gene Proteins 0.000 description 1
- 101150075622 UL80 gene Proteins 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical class C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- ILYCZKOBLRJJSW-UHFFFAOYSA-N ethyl 2-amino-4-methylthiophene-3-carboxylate Chemical compound CCOC(=O)C=1C(C)=CSC=1N ILYCZKOBLRJJSW-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- IYIVBGQBEMSRLO-UHFFFAOYSA-N methyl 2-(4-iodophenyl)acetate Chemical compound COC(=O)CC1=CC=C(I)C=C1 IYIVBGQBEMSRLO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 108010092122 varicella-zoster virus protease Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
- C07D265/22—Oxygen atoms
Definitions
- the present invention relates to compounds which are of potential use as antiviral agents, pharmaceutical compositions containing them and their use in therapy.
- WO 96/19482 SmithKline Beecham pic
- WO 97/27200 SmithKline
- WO 96/37485 (G.D. Searle & Co.) describes 2-amino-benzoxazinones as herpesvirus protease inhibitors.
- Jarvest et al Bioorg. Med. Chem. Lett., (1996), 6(20), 2463-2466, describes benzoxazinone derivatives as herpesvirus protease inhibitors.
- WO 97/48707 (SmithKline Beecham pic, published after the priority date of this application) describes 2-substituted herpesvirus protease inhibitor 4H-3,l-benzoxazin-4- one, 4H-thieno[3,2-d][l,3]oxazin-4-one, and 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives.
- the present invention provides herpesvirus protease inhibitor 4H-3,l-benzoxazin-4-one, 4H-thieno[3,2-d][l,3]oxazin-4-one, or 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives which are 2-substituted by -C(XY)-R j , -C(XY)-C ⁇ 2 -R ⁇ , -C(XY)-C2H 4 -R l5 or -CX-CY-Ri wherein one of X and Y is hydrogen, halo or C ⁇ .
- alkyl and the other is hydrogen or C ⁇ .$ alkyl
- R is aryl or heteroaryl, substituted by ZR4 wherein Z is CO, NR x CO, NR x COCO, NR x COCH2, or NR x SO2 wherein R x is hydrogen or C g alkyl, and R4 is aryl or heteroaryl, substituted by NR z OH wherein R z is hydrogen or Cj.g alkyl; and pharmaceutically acceptable salts thereof; the derivatives are hereinafter referred to as compounds of formula (I).
- R3 and R There may be substituents in the 5- and 6-positions (designated R3 and R respectively) as well as the 2-substituent. These may be selected from halo, C ⁇ . alkyl, C ⁇ -6 alkoxy, C ⁇ .g alkylthio, amino optionally substituted by one or two C ⁇ .g alkyl or optionally substituted benzyl groups, hydroxy C ⁇ . ⁇ alkyl, C ⁇ _6 alkylcarbonyl, C ⁇ . alkoxycarbonyl, optionally substituted phenyl or R5ZCONH wherein Z is a bond, O, NH or NCOCH3, and R5CO is an acyl group where values of R5 include aryl, C ⁇ . ⁇ alkyl or aryl C ⁇ . alkyl; or R3 and R may be joined to form C3..8 polymethylene.
- the 5-substituent is methyl
- the 6-position is unsubstituted or the 6- substituent is CH ⁇ Ra, OCH2Rb > or NR ⁇ Rd wherein R a and Rt ⁇ are selected from hydrogen or a substituent, R ⁇ is ⁇ . alkyl and R f is C ⁇ _6 alkyl or substituted . alkyl or R ⁇ and R ⁇ are joined to form a heterocyclic ring, for example containing one or more heteroatoms selected from N, O and S.
- a particular value for the 6-substituent is 6- thiomorpholino.
- a further particular value for the 6-substituent is methyl.
- the substituents R a and Rt ⁇ may be selected from one or more of halo, trifiuoromethyl, cyano, Cj.6 alkyl, C ⁇ . ⁇ alkoxy, aryloxy, aryl(C ⁇ _6 alkyl)oxy,
- C ⁇ _6 alkylthio amino optionally substituted by one or two ⁇ . alkyl or optionally substituted benzyl groups, hydroxy, C ⁇ . alkylcarbonyl, C ⁇ . alkoxycarbonyl, trifluoromethylcarbonyl, optionally substituted phenyl or RgZCOY wherein Z is a bond, O, NH or NCOCH3, and R e CO is an acyl group where values of R e include aryl, C ⁇ . ⁇ alkyl, aryl C ⁇ . alkyl, or heteroaryl C ⁇ . ⁇ alkyl; and Y is O or NRf wherein Rf is hydrogen, Cj.g alkyl, aryl, or aryl C ⁇ .
- R e and Rf may together form C2-6 polymethylene; or R a and Rt ⁇ may be selected from Cj.g alkyl or C2-6 alkenyl substituted by one or more of the values listed above for substituents R a and Rt ⁇ .
- R ⁇ substituents are as defined for R a and Rt ⁇ above.
- Values for R and R4 when joined to form a heterocyclic ring include optionally substituted piperidine, pyrrolidine, azetidine, morpholine, and piperazine. Suitable substituents are as listed above for R a and R ⁇ ,, or the heterocyclic ring may contain an exocyclic optionally protected carbonyl group.
- the substituents may be as described above for the 4H-thieno[2,3-d][l,3]oxazin- -one ring system, except that the description for the 5-substituent applies to the -substituent.
- C ⁇ _g alkyl or C ⁇ _ ⁇ alkyl containing groups include C ⁇ . ⁇ , particularly C1.4, branched, straight chained and/or cyclic and/or primary, secondary or tertiary alkyl, as appropriate.
- C1.4 alkyl groups include methyl, ethyl, n- and w ⁇ -propyl, n-, iso-, sec- and tert-butyl.
- Cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- Alkenyl includes all suitable values including E and Z forms.
- Aryl includes phenyl and naphthyl optionally substituted by one or more substituents.
- substituents may be selected from halo, Cj.g alkyl, C ⁇ . ⁇ alkoxy, C ⁇ . alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, Cj.g alkylcarbonyl, C ⁇ . alkylcarbonyloxy, amino optionally substituted by one or two C ⁇ . alkyl groups, and acetylamino.
- Heteroaryl includes 5- or 6-membered monocyclic heteroaryl or 9- or 10- membered fused bicyclic heteroaryl linked through carbon, for example containing 1, 2 or 3 heteroatoms selected from N, O and S.
- Monocyclic heteroaryl groups include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole and thiazole (all possible isomers).
- Bicyclic heteroaryl groups include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and woquinolyl (all possible isomers).
- Heteroaryl may be optionally substituted by one or more substituents. These may be selected from those described above for aryl substituents.
- Halo includes fluoro, chloro, bromo and iodo.
- a particular 2-substituent which may be mentioned is -C(XY)-R j .
- Examples of -C(XY)- include CH 2 , CH(CH 3 ), CH(C H 5 ), C(CH 3 ) 2 , and CC1(CH3), a particular example being CH2-
- R ⁇ examples include phenyl ortho, meta, ox para substituted by ZR4, and thienyl 2- or 3-substituted by ZR4, a particular example being phenyl ortho, meta, or para substituted by ZR4.
- Z are CO and NR x CO.
- R x is hydrogen.
- R4 examples include phenyl, 2- or 3-thienyl or furanyl, 1-, 3- or 4-pyridyl, and thiazolyl, substituted by NR z OH, a particular example being phenyl substituted by NR z OH.
- R z is preferably hydrogen.
- Examples of pharmaceutically acceptable salts of the compound of formula (I) are included in the invention, as appropriate.
- the compounds wherein X and Y are different exist in more than one enantiomeric form.
- the invention extends to both of these forms and to mixtures thereof, including racemates.
- the compounds of formula (I) including their pharmaceutically acceptable salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.
- the compounds are prepared by activating an R ⁇ containing or R ⁇ precursor containing carboxylic acid by standard coupling procedures such as: i) formation of an activated ester with a carbodiimide or other coupling reagent and a moiety such as 1-hydroxybenzotriazole, or ii) formation of a mixed anhydride with a reagent such as wobutyl chloro formate and reacting with a 2-aminothiophene 3-carboxylic acid or ester.
- standard coupling procedures such as: i) formation of an activated ester with a carbodiimide or other coupling reagent and a moiety such as 1-hydroxybenzotriazole, or ii) formation of a mixed anhydride with a reagent such as wobutyl chloro formate and reacting with a 2-aminothiophene 3-carboxylic acid or ester.
- the intermediate amide may be isolated or the crude reaction product cyclised directly.
- Reagents suitable for the cyclisation of the thiophene acid derivatives include coupling agents or dehydrating agents such as carbodiimides, acetic anhydride or sulphonyl chlorides.
- Reagents suitable for the cyclisation of the thiophene ester derivatives include triphenylphosphine/carbon tetrachloride. It will be appreciated that according to the nature of the 5- and 6- substituents in the required product, the cyclisation may occur prior to or after introduction modification of the relevant substituent(s).
- R may be modified after the oxazinone formation. Such modifications include alkylation of X or Y when hydrogen and interconversion of aryl or heteroaryl substituents.
- Suitable R precursors when Z is NR x CO, NR x COCO, NR x COCH2, or NR x SO2 are the corresponding compounds of formula (I) wherein R is Ri' which is substituted aryl or heteroaryl.
- Examples of Rj' include phenyl substituted by nitro, which is then reduced, followed by conversion to the appropriate value of ZR4 by conventional methods.
- Ri ' is phenyl substituted by halo, such as iodo, followed by conversion to the appropriate value of ZR4 by conventional methods, such as the boronic acid route described in Examples 2 and 3 hereinafter.
- substituent on R4 in the compound of formula (I) is convertible, for example, a compound of formula (I) in which R4 is substituted by NHOH may be prepared by reduction of the corresponding compound in which R4 is substituted by nitro.
- compositions of the invention may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid.
- the compounds of the invention are of potential use in the treatment of infections caused by herpesviruses such as herpes simplex types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus, especially cytomegalovirus and/or herpes simplex 2 (HSV-2).
- herpesviruses such as herpes simplex types 1 and 2, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus, especially cytomegalovirus and/or herpes simplex 2 (HSV-2).
- the compounds of the invention may be formulated for use in a pharmaceutical composition. Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.
- a composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet or capsule.
- any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk.
- the composition may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension.
- Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups.
- the compounds may also be presented with a sterile liquid carrier for injection.
- composition may possibly also be formulated for topical application to the skin or eyes.
- the composition may be in the form of a cream, lotion or ointment.
- These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopoeia.
- composition for application to the eyes may be a conventional eye-drop composition well known in the art, or an ointment composition.
- the composition of the invention is in unit dosage form or in some other form that may be administered in a single dose.
- a suitable dosage unit might contain from 50 mg to 1 g of active ingredient, for example 100 to 500 mg.
- Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day.
- An effective dose of compound of formula (I) will generally be in the range of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day. No unacceptable toxicological effects are indicated at the above described dosage levels.
- the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of viral diseases caused by herpesviruses.
- the invention also provides a method of treating viral infections in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular for the treatment of viral infections.
- the mixture was hydrogenated under 50psi of hydrogen at ambient temp for 5 hrs.
- the mixture was filtered through CELITE then evaporated to an orange oil which was purified by chromatography on silica gel (dichloromethane / ether - gradient elution from 0-12% ether) to give the title compound as a yellow solid (435 mg, 60%) mp 136- 7°C.
- reaction mixture was diluted with water (100 ml), and extracted with ethyl acetate (3x100 ml). The combined organic solutions were washed with saturated NaHCO3 and brine, dried (Na2SO4) and evaporated to dryness. The residue was washed with methanol (20 ml) to give the required product as a pale yellow solid.
- the isolated product mixture was chromatographed on silica gel (gradient of 0-25% ether in dichloromethane) and further purified by crystallization from acetonitrile to give the title compound as a pale yellow solid.
- Ri phenyl meta substituted by 4-(N-hydroxyamino)benzoylamino ⁇ a) 5-Methyl-2-[3-(4-nitrophenylcarboxamido)benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-
- the enzyme used in the assay for HSN-2 consists of the proteolytically active domain of the HSN-2 UL26 homologue protein (amino acid residues 1 to 247).
- WO 95/06055 (SmithKline Beecham Corp.) describes the HSV-2 protease sequence.
- the enzyme used in the assay for CMV consists of the proteolytically active domain of the CMV UL80 protein (amino acid residues 1 to 256) with a mutation A143V.
- the enzyme used in the assay for VZV consists of the proteolytically active domain of the VZV gene 33 protein (amino acid residues 1 to 237).
- a quenched fluorescence based assay is used to generate IC50 data for compounds screened against HSV-2, VZV and CMV proteases.
- the cleavage of a quenched fluorescent (QF) peptide substrate by the protease yields an increase in measured fluorescence over the time of incubation.
- the assay currently uses a final volume of 200 ⁇ l of assay mixture in each well. However, volume additions and dilution steps can be altered to cope with any changes in starting and/or final concentrations for each assay component.
- the steps described below have been configured to run using a Beckman Biomek 2000 robot. Compounds for screening are made up as stock solutions in 100% DMSO. Four compounds in duplicate are arranged per plate for screening against all three proteases.
- the compound stock solution, in the first well, is serially diluted 1/1 (v/v) with DMSO to produce a 1000 fold decrease in stock concentration across the plate in 11 points.
- Eight wells are included containing 100% DMSO only for addition to four control and four blank wells on the reaction plate.
- the reaction plate is an opaque 96 well plate designed for use with a fluorometric plate reader.
- Compound/DMSO from the dilution plate are transferred to the reaction plate which already contains assay buffer.
- the type of assay buffer used depends on which of the proteases is being assessed in the screen. For HSV-2 and VZV proteases this is 50mM hepes/150mM ⁇ aCl lmM EDTA 0.01%PEG 3,400/0.8M sodium citrate* in 30% sucrose, pH 7.5
- CMN protease the 0.8M sodium citrate is omitted from the assay buffer. Each protease is stored at -20°C, thawed and stored on ice for ⁇ lhr. The protease stock is then diluted using the correct buffer to 5 OX the final concentration needed. The diluted protease stock is added to all but the four wells designed to be used as blanks. Buffer only is used in these wells. The final concentrations are 500nm, 20nm and 20nm for HSN-2, NZN and CMN respectively.
- the assay mixture is incubated at 27°C for 15 minutes.
- Solid QF peptide substrate is resuspended in 10% DMSO/water at 400mM. This is further diluted 1/10 with assay buffer and added to each well of the reaction plate to give the final concentration of 10 ⁇ M.
- FQ-7 peptide is used as the substrate for HSN-2 and NZN proteases.
- FQ-8 peptide is used as the substrate for CMN protease.
- FQ8 Dabs-RGNV ⁇ ASSALAKK-Dans
- the plate is read every 30 seconds with a Fluostar SLT fluorometric plate reader using Annelisa software, for 15 min at 27°C. Ex 355/Em 495nm. Data is transferred to Graphit software where rates of fluorescence are plotted against inhibitor concentrations. IC50 values are calculated for each of the four compounds against all three proteases.
- the compound of the Examples had an IC50 of ⁇ luM against CMN protease, the compound of Example 1 having preferred activity.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Herpesvirus protease inhibitor 4H-3,1-benzoxazin-4-one, 4H-thieno[3,2-d][1,3]oxazin-4-one, and 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives which are 2-substituted by -C(XY)-R1, -C(XY)-CH2-R1, -C(XY)-C2H4-R1, or -CX=CY-R1 wherein one of X and Y is hydrogen, halo or C1-6 alkyl and the other is hydrogen or C1-6 alkyl, and R1 is aryl or heteroaryl, substituted by ZR4 wherein Z is CO, NRxCO, NRxCOCO, NRxCOCH2, or NRxSO2 wherein Rx is hydrogen or C1-6 alkyl, and R4 is aryl or heteroaryl, substituted by NRzOH wherein Rz is hydrogen or C1-6 alkyl; and pharmaceutically acceptable salts thereof.
Description
ANTIVIRAL AGENTS
The present invention relates to compounds which are of potential use as antiviral agents, pharmaceutical compositions containing them and their use in therapy. WO 96/19482 (SmithKline Beecham pic) and WO 97/27200 (SmithKline
Beecham pic, published after the priority date of this application) describe 2-substituted herpesvirus protease inhibitor 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives.
WO 96/37485 (G.D. Searle & Co.) describes 2-amino-benzoxazinones as herpesvirus protease inhibitors. Jarvest et al, Bioorg. Med. Chem. Lett., (1996), 6(20), 2463-2466, describes benzoxazinone derivatives as herpesvirus protease inhibitors.
WO 97/48707 (SmithKline Beecham pic, published after the priority date of this application) describes 2-substituted herpesvirus protease inhibitor 4H-3,l-benzoxazin-4- one, 4H-thieno[3,2-d][l,3]oxazin-4-one, and 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives.
It has now been discovered that certain benzoxazinone and thienoxazinone derivatives are potentially useful in the treatment of infection caused by herpesviruses.
Accordingly, the present invention provides herpesvirus protease inhibitor 4H-3,l-benzoxazin-4-one, 4H-thieno[3,2-d][l,3]oxazin-4-one, or 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives which are 2-substituted by -C(XY)-Rj, -C(XY)-CΗ2-Rι, -C(XY)-C2H4-Rl5 or -CX-CY-Ri wherein one of X and Y is hydrogen, halo or C\. alkyl and the other is hydrogen or C\ .$ alkyl, and R is aryl or heteroaryl, substituted by ZR4 wherein Z is CO, NRxCO, NRxCOCO, NRxCOCH2, or NRxSO2 wherein Rx is hydrogen or C g alkyl, and R4 is aryl or heteroaryl, substituted by NRzOH wherein Rz is hydrogen or Cj.g alkyl; and pharmaceutically acceptable salts thereof; the derivatives are hereinafter referred to as compounds of formula (I).
The 4H-thieno[2,3-d][l,3]oxazin-4-one ring system is numbered thus:
There may be substituents in the 5- and 6-positions (designated R3 and R respectively) as well as the 2-substituent. These may be selected from halo, C\. alkyl, C\-6 alkoxy, C^.g alkylthio, amino optionally substituted by one or two C^.g alkyl or optionally substituted benzyl groups, hydroxy C\.β alkyl, C\_6 alkylcarbonyl, C\. alkoxycarbonyl, optionally substituted phenyl or R5ZCONH wherein Z is a bond, O, NH or NCOCH3, and R5CO is an acyl group where values of R5 include aryl, C\.β alkyl or aryl C\. alkyl; or R3 and R may be joined to form C3..8 polymethylene.
Preferably the 5-substituent is methyl, and the 6-position is unsubstituted or the 6- substituent is CH^Ra, OCH2Rb> or NRςRd wherein Ra and Rtø are selected from hydrogen or a substituent, Rς is \. alkyl and Rf is C\_6 alkyl or substituted . alkyl or Rς and R^ are joined to form a heterocyclic ring, for example containing one or more heteroatoms selected from N, O and S. A particular value for the 6-substituent is 6- thiomorpholino. A further particular value for the 6-substituent is methyl.
The substituents Ra and Rtø may be selected from one or more of halo, trifiuoromethyl, cyano, Cj.6 alkyl, C^.β alkoxy, aryloxy, aryl(Cι_6 alkyl)oxy,
Cι_6 alkylthio, amino optionally substituted by one or two \. alkyl or optionally substituted benzyl groups, hydroxy, C\. alkylcarbonyl, C\. alkoxycarbonyl, trifluoromethylcarbonyl, optionally substituted phenyl or RgZCOY wherein Z is a bond, O, NH or NCOCH3, and ReCO is an acyl group where values of Re include aryl, C\.β alkyl, aryl C\. alkyl, or heteroaryl C\.β alkyl; and Y is O or NRf wherein Rf is hydrogen, Cj.g alkyl, aryl, or aryl C\. alkyl, or Re and Rf may together form C2-6 polymethylene; or Ra and Rtø may be selected from Cj.g alkyl or C2-6 alkenyl substituted by one or more of the values listed above for substituents Ra and Rtø.
Values of R^ substituents are as defined for Ra and Rtø above. Values for R and R4 when joined to form a heterocyclic ring include optionally substituted piperidine, pyrrolidine, azetidine, morpholine, and piperazine. Suitable substituents are as listed above for Ra and R^,, or the heterocyclic ring may contain an exocyclic optionally protected carbonyl group.
The substituents may be as described above for the 4H-thieno[2,3-d][l,3]oxazin- -one ring system, except that the description for the 5-substituent applies to the -substituent.
The 4H-3,l-benzoxazin-4-one ring system is numbered thus:
The substituents may be as described above for the 4H-thieno[2,3-d][l,3]oxazin- 4-one ring system, except that the description for the 5- and 6-substituents applies to substituents selected from 5-, 6-, 7-, and 8-. Examples of C \ _g alkyl or C \ _β alkyl containing groups include C\.β, particularly C1.4, branched, straight chained and/or cyclic and/or primary, secondary or tertiary alkyl, as appropriate. C1.4 alkyl groups include methyl, ethyl, n- and wø-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alkenyl includes all suitable values including E and Z forms.
Aryl includes phenyl and naphthyl optionally substituted by one or more substituents. Such substituents may be selected from halo, Cj.g alkyl, C\.β alkoxy, C\. alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, Cj.g alkylcarbonyl, C\. alkylcarbonyloxy, amino optionally substituted by one or two C\. alkyl groups, and acetylamino.
Heteroaryl includes 5- or 6-membered monocyclic heteroaryl or 9- or 10- membered fused bicyclic heteroaryl linked through carbon, for example containing 1, 2 or 3 heteroatoms selected from N, O and S. Monocyclic heteroaryl groups include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole and thiazole (all
possible isomers). Bicyclic heteroaryl groups include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and woquinolyl (all possible isomers).
Heteroaryl may be optionally substituted by one or more substituents. These may be selected from those described above for aryl substituents. Halo includes fluoro, chloro, bromo and iodo.
A particular 2-substituent which may be mentioned is -C(XY)-Rj . Examples of -C(XY)- include CH2, CH(CH3), CH(C H5), C(CH3)2, and CC1(CH3), a particular example being CH2-
Examples of R\ include phenyl ortho, meta, ox para substituted by ZR4, and thienyl 2- or 3-substituted by ZR4, a particular example being phenyl ortho, meta, or para substituted by ZR4.
Particular examples of Z are CO and NRxCO. An example of Rx is hydrogen.
Examples of R4 include phenyl, 2- or 3-thienyl or furanyl, 1-, 3- or 4-pyridyl, and thiazolyl, substituted by NRzOH, a particular example being phenyl substituted by NRzOH.
Rz is preferably hydrogen.
R4 when phenyl may also be optionally substituted as described hereinbefore for aryl substituents. Examples of pharmaceutically acceptable salts of the compound of formula (I) are included in the invention, as appropriate.
The compounds wherein X and Y are different exist in more than one enantiomeric form. The invention extends to both of these forms and to mixtures thereof, including racemates. The compounds of formula (I) including their pharmaceutically acceptable salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.
The compounds are prepared by activating an R^ containing or R\ precursor containing carboxylic acid by standard coupling procedures such as: i) formation of an activated ester with a carbodiimide or other coupling reagent and a moiety such as 1-hydroxybenzotriazole, or
ii) formation of a mixed anhydride with a reagent such as wobutyl chloro formate and reacting with a 2-aminothiophene 3-carboxylic acid or ester.
The intermediate amide may be isolated or the crude reaction product cyclised directly. Reagents suitable for the cyclisation of the thiophene acid derivatives include coupling agents or dehydrating agents such as carbodiimides, acetic anhydride or sulphonyl chlorides. Reagents suitable for the cyclisation of the thiophene ester derivatives include triphenylphosphine/carbon tetrachloride. It will be appreciated that according to the nature of the 5- and 6- substituents in the required product, the cyclisation may occur prior to or after introduction modification of the relevant substituent(s).
It will be appreciated that R may be modified after the oxazinone formation. Such modifications include alkylation of X or Y when hydrogen and interconversion of aryl or heteroaryl substituents. Suitable R precursors when Z is NRxCO, NRxCOCO, NRxCOCH2, or NRxSO2 are the corresponding compounds of formula (I) wherein R is Ri' which is substituted aryl or heteroaryl. Examples of Rj' include phenyl substituted by nitro, which is then reduced, followed by conversion to the appropriate value of ZR4 by conventional methods. When Z is CO a further example of Ri ' is phenyl substituted by halo, such as iodo, followed by conversion to the appropriate value of ZR4 by conventional methods, such as the boronic acid route described in Examples 2 and 3 hereinafter. Similarly, the substituent on R4 in the compound of formula (I) is convertible, for example, a compound of formula (I) in which R4 is substituted by NHOH may be prepared by reduction of the corresponding compound in which R4 is substituted by nitro.
The compounds which are derivatives of 4H-3,l-benzoxazin-4-one and 4H-thieno[3,2-d][ 1 ,3]oxazin-4-one may be prepared by analogous methods and/or the methods described in the aforementioned references.
Pharmaceutically acceptable salts may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid. The compounds of the invention are of potential use in the treatment of infections caused by herpesviruses such as herpes simplex types 1 and 2, varicella-zoster
virus, Epstein-Barr virus and cytomegalovirus, especially cytomegalovirus and/or herpes simplex 2 (HSV-2).
The compounds of the invention may be formulated for use in a pharmaceutical composition. Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.
A composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet or capsule. When the composition is in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The composition may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. The compounds may also be presented with a sterile liquid carrier for injection.
The composition may possibly also be formulated for topical application to the skin or eyes.
For topical application to the skin, the composition may be in the form of a cream, lotion or ointment. These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopoeia.
The composition for application to the eyes may be a conventional eye-drop composition well known in the art, or an ointment composition.
Preferably, the composition of the invention is in unit dosage form or in some other form that may be administered in a single dose. A suitable dosage unit might contain from 50 mg to 1 g of active ingredient, for example 100 to 500 mg.
Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day. An effective dose of compound of formula (I) will generally be in the range of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day.
No unacceptable toxicological effects are indicated at the above described dosage levels.
The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of viral diseases caused by herpesviruses.
The invention also provides a method of treating viral infections in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular for the treatment of viral infections.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Examples illustrate the invention and the following assay description illustrates the herpes protease inhibition activity.
Intermediate Preparation 1 2-Amino-4-methyIthiophene-3-carboxyIic acid
To a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (10.0 g, 54.0 mrnol) in a mixture of dioxane (37.5 ml), methanol (25 ml) and water (12.5 ml) was added lithium hydroxide hydrate (11.3 g, 270 mmol). The mixture was heated at 70°C for 14 hrs then partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase was acidified by addition of 10% citric acid solution (500 ml) and the product was extracted into dichloromethane (2 x 500 ml, 1 x 250 ml). The combined organic solutions were dried (MgSO4), filtered and evaporated to give 2-amino-4- methylthiophene-3-carboxylic acid as a tan coloured solid (5.9 g, 69%). lH NMR δ (DMSO-d6): 2.16 (3H, s, CH3), 5.89 (1H, s, 5-H), 7.26 (2H, br s, D2O exchangeable, NH ), 11.90 (1H, br s, D2O exchangeable, CO2H).
Intermediate Preparation 2 4-(3-Nitrobenzoyl)phenylacetic acid a) Methyl 4-iodophenylacetate (16.0 g, 58 rnmol), 3-nitrophenylboronic acid (9.67 g, 58 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.40 g) and potassium carbonate (24.0 g, 174 mmol) in anisole (250 ml) were heated at 90 - 95°C in an atmosphere of carbon monoxide for 22 hrs. The mixture was cooled to room temperature and filtered through CELITE, washing well with ether. The solvents were evaporated to give a red oil which was purified by chromatography on silica gel (petroleum ether / ethyl acetate) to give methyl 4-(3-nitrobenzoyl)phenylacetate as a light brown solid (6.15 g, 35%) mp 73-5°C.
!H NMR δ (CDCI3): 3.74 (5H, s), 7.42 (2H, d, J=8Hz), 7.6 (3H, m), 8.13 (1H, m), 8.46 (1H, s), 8.62 (1H, s). b) Methyl 4-(3-nitrobenzoyl)phenylacetate (3.29 g, 11 mmol) was dissolved in warm methanol (100 ml), cooled to 30°C and IN NaOH (22 ml) added. The solution was stirred at ambient temperature for 2 hrs, the methanol evaporated and water (50 ml) added. The solution was washed with ether, filtered through CELITE then acidified to pH3 with dilute HCl. The precipitated solid was filtered off, washed with water and dried to give the title compound as a copper coloured solid (2.91 g, 93%) mp 142-4°C. 1H NMR δ (DMSO-d6): 3.83 (3H, s), 7.7 (2H, d, J=8Hz), 7.75 (2H, d, J=8Hz), 7.87 (1H, m,), 8.15 (1H, m), 8.43 (1H, s), 8.5 (1H, m).
Example 1
5-MethyI-2-[4-[3-(N-hydroxyamino)benzoyI]benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-4- one (El) {a 4H-thieno[2,3-d][l,3]oxazin-4-one wherein R2=Η, R3=CH3, X=H, Y=H, Ri = phenyl para substituted by 3-(N-hydroxyamino)benzoyl} a) 4-(3-Nitrobenzoyl)phenylacetic acid, (2.85 g, 10 mmol), hydroxybenzotriazole (1.35 g, 10 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g, 10 mmol) were stirred in dry DMF (50 ml) for 30 min. To the resulting solution was added 2-amino-4-methylthiophene-3-carboxylic acid (1.57 g, 10 mmol) and triethylamine (1.4 ml, 10 mmol) and the mixture stirred for 6 hrs. Further l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (1.92 g) was added and after 24 hrs a
second addition (1.92 g) made. After 18 hrs the mixture was added to water (200 ml) and EtOAc (200 ml), separated and the aqueous extracted with EtOAc (200 ml). The combined organic solutions were washed with saturated NaHCO3, water, brine, dried (MgSO4) and evaporated to a brown oil which was purified by chromatography on silica gel (CH2CI2). Trituration with EtOAc gave 5-methyl-2-[4-(3-nitrobenzoyl)benzyl]-4H- thieno-[2,3-d][l,3]-oxazin-4-one as a pale yellow solid (2.22 g, 55%) mp 173-4°C. *H NMR δ (CDCI3): 2.51 (3H, s), 4.09 (3H, s), 6.87 (1H, s), 7.56 (2H, d, J=8Hz), 7.7 (1H, m), 7.80 (2H, d, J=8Hz), 8.13 (1H, m), 8.46 (1H, m), 8.5 (1H, s). b) 5-Methyl-2-[4-(3-nitrobenzoyl)benzyl]-4H-thieno-[2,3-d]-[l,3]-oxazin-4-one (773 mg, 1.9 mmol) was dissolved in EtOAc (300 ml) and 10% palladium on charcoal (250 mg) added. The mixture was hydrogenated under 50psi of hydrogen at ambient temp for 5 hrs. The mixture was filtered through CELITE then evaporated to an orange oil which was purified by chromatography on silica gel (dichloromethane / ether - gradient elution from 0-12% ether) to give the title compound as a yellow solid (435 mg, 60%) mp 136- 7°C.
*H NMR δ (DMSO-dg): 2.41 (3H, s), 4.20 (2H, s), 7.09 (2H, m), 7.21 (1H, s), 7.3 (2H, m), 7.55 (2H, d), 7.72 (2H, d), 8.49 (1H, m), 8.55 (1H, s).
Example 2 5,6-Dimethyl-2-[4-[3-(N-hydroxyamino)benzoyl]benzyl]-4H-thieno-[2,3-d][l,3]- oxazin-4-one
(E2) {a 4H-thieno[2,3-d][l,3]oxazin-4-one wherein R2=CΗ3, R3=CH3, X=H, Y=H,
R\ = phenyl para substituted by 3-(N-hydroxyamino)benzoyl} a) A solution of 4-iodophenylacetic acid (5.24 g, 20 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (DEC.HC1, 3.83 g, 20 mmol) and hydroxybenzotriazole (2.71 g, 20 mmol) in dry DMF (100 ml) was stirred at room temperature under argon for 35 min prior to the addition of 2-amino-4,5-dimethyl- thiophene-3-carboxylic acid (3.42 g, 20 mmol) [prepared from the appropriate ethyl ester which was hydrolysed with lithium hydroxide in aqueous methanolic dioxan in an analogous procedure to that described for Intermediate Preparation 1] and triethylamine (2.8 ml, 20 mmol). The mixture was stirred at room temperature for 3.5 hrs prior to the addition of a further aliquot of DEC.HC1 (7.67 g, 40 mmol). The solution was stirred for
16 hrs before being diluted with water (2 L) and extracted with ethyl acetate (3 x 500 ml). The combined organic solutions were washed with water (2 L) and brine (2 L), dried (MgSO4) and evaporated. The residual solid was chromatographed on silica gel using dichloromethane as eluent to afford 5,6-dimethyl-2-(4-iodobenzyl)-4H-thieno- [2,3-d][l,3]-oxazin-4-one as a solid, mp 146-7°C, following trituration with hexane. *H NMR δ (CDC13): 2.38 (6H, s), 3.89 (2H, s), 7.13 (2H, d), 7.66 (2H, d). b) A mixture of 5,6-dimethyl-2-(4-iodobenzyl)-4H-thieno-[2,3-d][l,3]-oxazin-4-one (1.985 g, 5 mmol), 3-mtrobenzeneboronic acid (0.915 g, 5 mmol), potassium carbonate (2.075 g, 15 mmol) and bis(triphenylphosphine)palladium(II) chloride (175 mg, 5 mol %) was suspended in anisole (30 ml) and degassed under vacuum. The flask was flushed with carbon monoxide and the degassing cycle repeated several times, finally leaving the reaction mixture under 1 atmosphere (balloon) of carbon monoxide. The mixture was heated at 80°C for 28 hrs, then cooled, diluted with water (500 ml) and extracted with dichloromethane (3 x 500 ml). The combined organic solutions were washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (ethyl acetate-dichloromethane, 2:98 v/v) as eluent to afford 5,6-dimethyl-2-[4-(3- nitrobenzoyl)benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-4-one, mp 182-3°C. !H NMR δ (CDCI3): 2.40 (6H, s), 4.07 (2H, s), 7.55 (2H, d), 7.70 (1H, t), 7.80 (2H, d), 8.10 (1H, d), 8.42 (1H, dm), 8.60 (lH,m). c) The title compound was prepared from 5,6-dimethyl-2-[4-(3- nitrobenzoyl)benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-4-one (0.294 g, 0.7 mmol) by a procedure analogous to that described for Example lb) and purified by chromatography on silica gel (ether-dichloromethane, 5:95 v/v) as eluent. iH NMR δ (DMSO-d6): 2.32 (3H, s), 2.38 (3H, s), 4.18 (2H, s), 7.05-7.75 (8H, m), 8.40- 8.60 (2H, br, exchanged with D2O).
Example 3
5-Methyl-2-[3-[3-(N-hydroxyamino)phenylcarboxamido]benzyl]-4H-thieno- [2,3-d] [l,3]-oxazin-4-one (E3) {a 4H-thieno[2,3-d][l ,3]oxazin-4-one wherein R2=Η, R3=CH3, X=H, Y=H, Ri = phenyl meta substituted by 3-(N-hydroxyamino)benzoylamino}
a) 5-Methyl-2-[3-(3-nitrophenylcarboxamido)benzyl]-4H-thieno-[2,3-d] [ 1 ,3]-oxazin- 4-one was prepared from 5-methyl-2-(3-aminobenzyl)-4H-thieno-[2,3-d][l,3]-oxazin-4- one (0.58 g, 2.13 mmol) [prepared by reducing the corresponding 3-nitrobenzyl compound, which was prepared as described for compounds of formula (I), using the appropriate carboxylic acid] and 3-nitrobenzoic acid (0.356 g, 2.13 mmol) by standard EDC coupling methodology (with HOBT in dimethylformamide). The reaction mixture was diluted with water (100 ml), and extracted with ethyl acetate (3x100 ml). The combined organic solutions were washed with saturated NaHCO3 and brine, dried (Na2SO4) and evaporated to dryness. The residue was washed with methanol (20 ml) to give the required product as a pale yellow solid.
!H NMR δ (DMSO-d6): 2.41 (3H, s), 4.08 (2H, s), 7.15 (IH, d), 7.30 (IH, s), 7.38 (IH, t), 7.70-7.90 (3H, m), 8.42 (2H, m), 8.79 (IH, s), 10.62 (IH, s). b) The title compound was prepared from 5-methyl-2-[3-(3- nitrophenylcarboxamido)benzyl]-4H-thieno[2,3-d][l,3]oxazin-4-one (0.25 g, 0.59 mmol) by a procedure similar to that described for Example lb), with a reaction time of 29 hrs.
The isolated product mixture was chromatographed on silica gel (gradient of 0-25% ether in dichloromethane) and further purified by crystallization from acetonitrile to give the title compound as a pale yellow solid.
*H NMR δ (DMSO-d6): 2.41 (3H, s), 4.05 (2H, s), 6.95-7.15 (2H, overlapping m), 7.2- 7.45 (5H, overlapping m), 7.65-7.80 (2H, m), 8.45 (IH, d, exchanged with D2O), 8.49
(IH, s, exchanged with D2O), 10.20 (IH, s, partially exchanged with D2O).
Example 4 5-Methyl-2-[3-[4-(N-hydroxyamino)phenyIcarboxamido]benzyl]-4H-thieno- [2,3-d][l,3]-oxazin-4-one
(E4) {a 4H-thieno[2,3-d][l,3]oxazin-4-one wherein R2=Η, R3=CH3, X=H, Y=H,
Ri = phenyl meta substituted by 4-(N-hydroxyamino)benzoylamino} a) 5-Methyl-2-[3-(4-nitrophenylcarboxamido)benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-
4-one was prepared from 5-methyl-2-(3-aminobenzyl)-4H-thieno-[2,3-d][l,3]-oxazin-4- one (0.58 g, 2.13 mmol) [prepared by reducing the corresponding 3-nitrobenzyl compound, which was prepared as described for compounds of formula (I), using the appropriate carboxylic acid] and 4-nitrobenzoic acid (0.356 g, 2.13 mmol) by standard
EDC coupling methodology (with HOBT in dimethylformamide). The resulting white solid was collected, washed with dichloromethane and methanol and dried in vacuo. IH NMR δ (CDCI3+CD3OD): 2.49 (3H, s), 4.01 (2H, s), 6.88 (IH, s), 7.20 (IH, d), 7.37 (IH, t), 7.64 (IH, s), 7.79 (IH, d), 8.11 (2H, d), 8.33 (2H, d). b) The title compound was prepared from 5-methyl-2-[3-(4- nitrophenylcarboxamido)benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-4-one (0.25 g, 0.59 mmol) by a procedure similar to that described for Example lb), with a reaction time of 1.75 hrs. The isolated product mixture was purified by crystallization from acetonitrile and further purified by chromatography on silica gel (gradient of 0-20% ether in dichloromethane) to give the title compound as a white solid.
IH NMR δ (DMSO-d6): 2.41 (3H, s), 4.04 (2H, s), 6.86 (2H, d), 7.06 (IH, d), 7.22-7.39 (2H, m), 7.63-7.78 (2H, m) partially overlapping with 7.82 (2H, d), 8.57 (IH, d, exchanged with D2O), 8.79 (IH, s, exchanged with D2O), 9.96 (IH, s, partially exchanged with D2O).
Example 5
5-Methyl-2-[4-[4-(N-hydroxyamino)benzoyl]benzyl]-4H-thieno[2,3-d][l,3]oxazin-4- one
(E4) {a 4H-thieno[2,3-d][l,3]oxazin-4-one wherein R2=Η, R3=CH3, X=H, Y=H, R\ = phenyl para substituted by 4-(N-hydroxyamino)benzoylarnino}
5-Methyl-2-[4-(4-nitrobenzoyl)benzyl]-4H-thieno[2,3-d] [ 1 ,3]oxazin-4-one [prepared in a similar manner to Example la)] (406 mg, 1 mmol) was dissolved in THF (20 ml) and a solution of sodium hypophosphite (264 mg, 3 mmol) in water (10 ml) was added. 5% Palladium on charcoal (30 mg) was added under an atmosphere of argon and the mixture stirred at room temp for lhr. The mixture was filtered through CELITE then water (50 ml) and dichloromethane (100 ml) were added, the layers separated and the organic solutions washed with water, dried (MgSO4) and evaporated to a brown solid. This was boiled in dichloromethane (50 ml), cooled to RT, filtered and the mother liquor chromatographed on silica gel (dichloromethane / ether) to give the title compound as a light brown solid (79 mg, 20%) mp 169-71°C. lH NMR δ (DMSO-d6): 2.41 (3H, s), 4.18 (2H, s), 6.86 (2H, d, J=9Hz), 7.29 (IH, s), 7.52 (2H, d, J=8Hz), 7.63 (4H, m), 8.73 (IH, m), 9.11 (IH, s).
Quenched fluorescence assay for protease inhibition
Compounds are assayed in the following way:
The enzyme used in the assay for HSN-2 consists of the proteolytically active domain of the HSN-2 UL26 homologue protein (amino acid residues 1 to 247).
WO 95/06055 (SmithKline Beecham Corp.) describes the HSV-2 protease sequence. The enzyme used in the assay for CMV consists of the proteolytically active domain of the CMV UL80 protein (amino acid residues 1 to 256) with a mutation A143V. The enzyme used in the assay for VZV consists of the proteolytically active domain of the VZV gene 33 protein (amino acid residues 1 to 237).
A quenched fluorescence based assay is used to generate IC50 data for compounds screened against HSV-2, VZV and CMV proteases. The cleavage of a quenched fluorescent (QF) peptide substrate by the protease yields an increase in measured fluorescence over the time of incubation. The assay currently uses a final volume of 200 μl of assay mixture in each well. However, volume additions and dilution steps can be altered to cope with any changes in starting and/or final concentrations for each assay component. The steps described below have been configured to run using a Beckman Biomek 2000 robot. Compounds for screening are made up as stock solutions in 100% DMSO. Four compounds in duplicate are arranged per plate for screening against all three proteases. The compound stock solution, in the first well, is serially diluted 1/1 (v/v) with DMSO to produce a 1000 fold decrease in stock concentration across the plate in 11 points. Eight wells are included containing 100% DMSO only for addition to four control and four blank wells on the reaction plate. The reaction plate is an opaque 96 well plate designed for use with a fluorometric plate reader. Compound/DMSO from the dilution plate are transferred to the reaction plate which already contains assay buffer. The type of assay buffer used depends on which of the proteases is being assessed in the screen. For HSV-2 and VZV proteases this is 50mM hepes/150mM ΝaCl lmM EDTA 0.01%PEG 3,400/0.8M sodium citrate* in 30% sucrose, pH 7.5
*For CMN protease the 0.8M sodium citrate is omitted from the assay buffer.
Each protease is stored at -20°C, thawed and stored on ice for ~lhr. The protease stock is then diluted using the correct buffer to 5 OX the final concentration needed. The diluted protease stock is added to all but the four wells designed to be used as blanks. Buffer only is used in these wells. The final concentrations are 500nm, 20nm and 20nm for HSN-2, NZN and CMN respectively.
The assay mixture is incubated at 27°C for 15 minutes.
Solid QF peptide substrate is resuspended in 10% DMSO/water at 400mM. This is further diluted 1/10 with assay buffer and added to each well of the reaction plate to give the final concentration of 10 μM. FQ-7 peptide is used as the substrate for HSN-2 and NZN proteases. FQ-8 peptide is used as the substrate for CMN protease. FQ7: Dabs-DΝANEASSKAPLK-Dans FQ8: Dabs-RGNVΝASSALAKK-Dans
The plate is read every 30 seconds with a Fluostar SLT fluorometric plate reader using Annelisa software, for 15 min at 27°C. Ex 355/Em 495nm. Data is transferred to Graphit software where rates of fluorescence are plotted against inhibitor concentrations. IC50 values are calculated for each of the four compounds against all three proteases.
The results were as follows:
Results
The compound of the Examples had an IC50 of < luM against CMN protease, the compound of Example 1 having preferred activity.
Claims
1. Herpes protease inhibitor 4H-3,l-benzoxazin-4-one, 4H-thieno[3,2-d][l,3]oxazin- 4-one, or 4H-thieno[2,3-d][l,3]oxazin-4-one derivatives which are 2-substituted by -C(XY)-Rι , -C(XY)-CΗ2-Rι , -C(XY)-C2H4-R1 , or -CX=CY-Ri wherein one of X and Y is hydrogen, halo or C\.β alkyl and the other is hydrogen or Ci _g alkyl, and Ri is aryl or heteroaryl, substituted by ZR4 wherein Z is CO, NRxCO, NRxCOCO, NRxCOCH2, or NRxSθ2 wherein Rx is hydrogen or C\.β alkyl, and R4 is aryl or heteroaryl, substituted by NRzOH wherein Rz is hydrogen or C\.β alkyl; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, which is a 4H-thieno[2,3-d][l,3]oxazin-4-one derivative wherein the ring system, numbered thus:
is optionally substituted in the 5- and 6-positions (designated R3 and R2 respectively) as well as the 2-substituent, wherein R3 and R2 when present are selected from halo, C\.β alkyl, C\.β alkoxy, C\.β alkylthio, amino optionally substituted by one or two C\.β alkyl or optionally substituted benzyl groups, hydroxy C\.β alkyl, C\.β alkylcarbonyl, C\.β alkoxycarbonyl, optionally substituted phenyl or R5ZCONΗ wherein Z is a bond, O, NH or NCOCH3, and R5CO is an acyl group where values of R5 include aryl, C .β alkyl or aryl Ci .5 alkyl; or R3 and R2 may be joined to form C3.8 polymethylene.
3. A compound according to claim 2, wherein the 5-substituent R3 is methyl, and the 6-position is unsubstituted or the 6-substituent R2 is CH2Ra, OCH2RD> or NRςRd wherein Ra and Rtø are selected from hydrogen or a substituent, RQ is C\.β alkyl and R is C\.β alkyl or substituted C\.β alkyl or Rς and R^ are joined to form a heterocyclic ring containing one or more heteroatoms selected from N, O and S.
4. A compound according to any one of the preceding claims, wherein Ri is phenyl ortho, meta, or para substituted by ZR4.
5. A compound according to any one of the preceding claims, wherein R4 is phenyl substituted by NRzOH.
6. A compound according to any one of the preceding claims, wherein Rz is hydrogen.
7. A compound selected from:
5-methyl-2-[4-[3-(N-hydroxyamino)benzoyl]benzyl]-4H-thieno-[2,3-d][l,3]-oxazin-4- one;
5,6-dimethyl-2-[4-[3-(N-hydroxyamino)benzoyl]benzyl]-4H-thieno-[2,3-d][l,3]-oxazin- 4-one; 5-methyl-2-[3-[3-(N-hydroxyamino)phenylcarboxamido]benzyl]-4H-thieno-[2,3-d][l,3]- oxazin-4-one;
5-methyl-2-[3-[4-(N-hydroxyamino)phenylcarboxamido]benzyl]-4H-thieno-[2,3-d][l,3]- oxazin-4-one; and
5-methyl-2-[4-[4-(N-hydroxyamino)benzoyl]benzyl]-4H-thieno[2,3-d][l,3]oxazin-4-one; or a pharmaceutically acceptable salt of any one thereof.
8. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable earner or excipient.
9. Use of a compound of according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of viral diseases caused by herpesviruses.
10. A method of treating viral infections in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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GB9707256.5 | 1997-04-10 | ||
GBGB9707256.5A GB9707256D0 (en) | 1997-04-10 | 1997-04-10 | Pharmaceuticals |
GBGB9710931.8A GB9710931D0 (en) | 1997-05-29 | 1997-05-29 | Pharmaceuticals |
GB9710931.8 | 1997-05-29 |
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WO1998045298A1 true WO1998045298A1 (en) | 1998-10-15 |
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PCT/GB1998/001021 WO1998045298A1 (en) | 1997-04-10 | 1998-04-07 | Antiviral agents |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003053944A1 (en) * | 2001-12-20 | 2003-07-03 | Osi Pharmaceuticals, Inc. | Pancreatic lipase inhibitor compounds, their synthesis and use |
WO2006026619A3 (en) * | 2004-08-30 | 2006-05-04 | Us Health | Inhibition of viruses using rnase h inhibitors |
JP2011121948A (en) * | 2003-12-26 | 2011-06-23 | Masatoshi Hagiwara | Method for regulating phosphorylation of sr protein, and antiviral agent containing activity regulator of sr protein as active ingredient |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996019482A1 (en) * | 1994-12-22 | 1996-06-27 | Smithkline Beecham Plc | Thienoxazinone derivatives useful as antiviral agents |
WO1997048707A1 (en) * | 1996-06-20 | 1997-12-24 | Smithkline Beecham Plc | 4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents |
-
1998
- 1998-04-07 WO PCT/GB1998/001021 patent/WO1998045298A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996019482A1 (en) * | 1994-12-22 | 1996-06-27 | Smithkline Beecham Plc | Thienoxazinone derivatives useful as antiviral agents |
WO1997048707A1 (en) * | 1996-06-20 | 1997-12-24 | Smithkline Beecham Plc | 4h-3,1-benzoxazin-4-one derivatives and analogs as antiviral agents |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003053944A1 (en) * | 2001-12-20 | 2003-07-03 | Osi Pharmaceuticals, Inc. | Pancreatic lipase inhibitor compounds, their synthesis and use |
JP2005518383A (en) * | 2001-12-20 | 2005-06-23 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | Pancreatic lipase inhibiting compounds, their synthesis and use |
US7064122B2 (en) | 2001-12-20 | 2006-06-20 | Osi Pharmaceuticals, Inc. | Pancreatic lipase inhibitor compounds, their synthesis and use |
EA009368B1 (en) * | 2001-12-20 | 2007-12-28 | Оси Фармасьютикалз, Инк. | Pancreatic lipase inhibitor compounds, their synthesis and use |
AU2002366810B2 (en) * | 2001-12-20 | 2009-06-11 | Osi Pharmaceuticals, Inc. | Pancreatic lipase inhibitor compounds, their synthesis and use |
JP2011121948A (en) * | 2003-12-26 | 2011-06-23 | Masatoshi Hagiwara | Method for regulating phosphorylation of sr protein, and antiviral agent containing activity regulator of sr protein as active ingredient |
JP4771468B2 (en) * | 2003-12-26 | 2011-09-14 | 正敏 萩原 | Method for controlling phosphorylation of SR protein and antiviral agent comprising SR protein activity regulator as active ingredient |
US8338362B2 (en) | 2003-12-26 | 2012-12-25 | Masatoshi Hagiwara | Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
US8816089B2 (en) | 2003-12-26 | 2014-08-26 | Masatoshi Hagiwara | Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity |
WO2006026619A3 (en) * | 2004-08-30 | 2006-05-04 | Us Health | Inhibition of viruses using rnase h inhibitors |
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