USRE49698E1 - Substituted dihydroquinazolines - Google Patents
Substituted dihydroquinazolines Download PDFInfo
- Publication number
- USRE49698E1 USRE49698E1 US16/934,363 US202016934363A USRE49698E US RE49698 E1 USRE49698 E1 US RE49698E1 US 202016934363 A US202016934363 A US 202016934363A US RE49698 E USRE49698 E US RE49698E
- Authority
- US
- United States
- Prior art keywords
- alkyl
- trifluoromethyl
- represents hydrogen
- cyano
- alkoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime, expires
Links
- 238000000034 method Methods 0.000 claims abstract description 179
- 230000008569 process Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 9
- 241000701022 Cytomegalovirus Species 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- 239000001257 hydrogen Substances 0.000 claims description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 71
- -1 cyano, hydroxyl Chemical group 0.000 claims description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 44
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 41
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 41
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 40
- 239000000460 chlorine Substances 0.000 claims description 40
- 229910052801 chlorine Inorganic materials 0.000 claims description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 239000011737 fluorine Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 18
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
- 239000012453 solvate Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 208000015181 infectious disease Diseases 0.000 claims description 11
- 241000700605 Viruses Species 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical group FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 4
- 241000700586 Herpesviridae Species 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- RIPYGTPGAMWYIX-UHFFFAOYSA-N methoxymethyl thiohypofluorite Chemical group COCSF RIPYGTPGAMWYIX-UHFFFAOYSA-N 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000007039 two-step reaction Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 238000011321 prophylaxis Methods 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 6
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 238000004128 high performance liquid chromatography Methods 0.000 description 86
- 239000000047 product Substances 0.000 description 76
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 30
- 239000012071 phase Substances 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 24
- 229910052796 boron Inorganic materials 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 238000000926 separation method Methods 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 16
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 15
- VVBXKASDRZXWON-UHFFFAOYSA-N N=[PH3] Chemical class N=[PH3] VVBXKASDRZXWON-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 235000019253 formic acid Nutrition 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- MAHHTTNCTSPTDY-RMKNXTFCSA-N methyl (e)-3-[3-fluoro-2-[[2-methoxy-5-(trifluoromethyl)phenyl]iminomethylideneamino]phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC(F)=C1N=C=NC1=CC(C(F)(F)F)=CC=C1OC MAHHTTNCTSPTDY-RMKNXTFCSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000000825 ultraviolet detection Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- QNCDLOWONNUWDO-UHFFFAOYSA-N methyl 2-[8-fluoro-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=C(F)C=C1 QNCDLOWONNUWDO-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- YMQVJIXUIXHEGG-UHFFFAOYSA-N 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene Chemical compound COC1=CC=C(C(F)(F)F)C=C1N=C=O YMQVJIXUIXHEGG-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000012894 fetal calf serum Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- VRVIKRZIQWEYFB-UHFFFAOYSA-N 1-(3,4-difluorophenyl)piperazine Chemical compound C1=C(F)C(F)=CC=C1N1CCNCC1 VRVIKRZIQWEYFB-UHFFFAOYSA-N 0.000 description 4
- KIFCSMQTGWVMOD-UHFFFAOYSA-N 1-(3-fluorophenyl)piperazine Chemical compound FC1=CC=CC(N2CCNCC2)=C1 KIFCSMQTGWVMOD-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- MOIKTZJYFUIZJP-QZQOTICOSA-N methyl (e)-3-[3-fluoro-2-[(triphenyl-$l^{5}-phosphanylidene)amino]phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC(F)=C1N=P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 MOIKTZJYFUIZJP-QZQOTICOSA-N 0.000 description 4
- UZVSOJSLYDCHQK-UHFFFAOYSA-N methyl 2-[2-[4-(3,4-difluorophenyl)piperazin-1-yl]-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=C(F)C(F)=C1 UZVSOJSLYDCHQK-UHFFFAOYSA-N 0.000 description 4
- JSCIYKMNXMGJPS-UHFFFAOYSA-N methyl 2-[8-fluoro-2-[4-(3-fluorophenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=CC(F)=C1 JSCIYKMNXMGJPS-UHFFFAOYSA-N 0.000 description 4
- IJXAXJJXOIKRMX-UHFFFAOYSA-N methyl 2-[8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-[4-(3-methylphenyl)piperazin-1-yl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=CC(C)=C1 IJXAXJJXOIKRMX-UHFFFAOYSA-N 0.000 description 4
- 150000002828 nitro derivatives Chemical class 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
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- 239000001023 inorganic pigment Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Chemical class 0.000 description 1
- 239000001630 malic acid Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- RJQACWDPFKYFPP-NSCUHMNNSA-N methyl (e)-3-(2-amino-3,5-difluorophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC(F)=CC(F)=C1N RJQACWDPFKYFPP-NSCUHMNNSA-N 0.000 description 1
- QSQJNLFKFYTKST-AATRIKPKSA-N methyl (e)-3-(2-amino-3-fluorophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC(F)=C1N QSQJNLFKFYTKST-AATRIKPKSA-N 0.000 description 1
- ZUWAWYZKDLQYNQ-HWKANZROSA-N methyl (e)-3-(2-amino-5-cyanophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC(C#N)=CC=C1N ZUWAWYZKDLQYNQ-HWKANZROSA-N 0.000 description 1
- WPRZRDBVRPVFQO-VOTSOKGWSA-N methyl (e)-3-(3-methoxy-2-nitrophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC(OC)=C1[N+]([O-])=O WPRZRDBVRPVFQO-VOTSOKGWSA-N 0.000 description 1
- IQCDHRRJYHIFOO-SNAWJCMRSA-N methyl (e)-3-(4-cyano-2-nitrophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(C#N)C=C1[N+]([O-])=O IQCDHRRJYHIFOO-SNAWJCMRSA-N 0.000 description 1
- OWVMDPCVFSKRGS-GORDUTHDSA-N methyl (e)-3-(5-fluoro-2-nitrophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC(F)=CC=C1[N+]([O-])=O OWVMDPCVFSKRGS-GORDUTHDSA-N 0.000 description 1
- GFBYTECBJSYFFJ-QZQOTICOSA-N methyl (e)-3-[2-cyano-6-[(triphenyl-$l^{5}-phosphanylidene)amino]phenyl]prop-2-enoate Chemical compound C1=CC=C(C#N)C(/C=C/C(=O)OC)=C1N=P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 GFBYTECBJSYFFJ-QZQOTICOSA-N 0.000 description 1
- XBBNKGUJKRTKJZ-CZIZESTLSA-N methyl (e)-3-[5-cyano-2-[(triphenyl-$l^{5}-phosphanylidene)amino]phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC(C#N)=CC=C1N=P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XBBNKGUJKRTKJZ-CZIZESTLSA-N 0.000 description 1
- IDWHLOBGCYWROH-LVZFUZTISA-N methyl (e)-3-[5-fluoro-2-[(triphenyl-$l^{5}-phosphanylidene)amino]phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC(F)=CC=C1N=P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IDWHLOBGCYWROH-LVZFUZTISA-N 0.000 description 1
- UAKBAQZEFKIISZ-UHFFFAOYSA-N methyl 2-[2-[4-(1,3-benzodioxol-5-yl)piperazin-1-yl]-8-fluoro-3-[3-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound C1CN(C=2C=C3OCOC3=CC=2)CCN1C1=NC2=C(F)C=CC=C2C(CC(=O)OC)N1C1=CC=CC(C(F)(F)F)=C1 UAKBAQZEFKIISZ-UHFFFAOYSA-N 0.000 description 1
- FAGKPPBCYQUKPS-UHFFFAOYSA-N methyl 2-[2-[4-(3-chlorophenyl)piperazin-1-yl]-8-fluoro-3-[3-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C=C(C=CC=2)C(F)(F)F)C=1N(CC1)CCN1C1=CC=CC(Cl)=C1 FAGKPPBCYQUKPS-UHFFFAOYSA-N 0.000 description 1
- SYMGSTOMNAOHHU-UHFFFAOYSA-N methyl 2-[3-(5-chloro-2-methoxyphenyl)-8-fluoro-2-[4-(4-fluorophenyl)piperazin-1-yl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(Cl)C=2)OC)C=1N(CC1)CCN1C1=CC=C(F)C=C1 SYMGSTOMNAOHHU-UHFFFAOYSA-N 0.000 description 1
- RHVXRSVSXRBAAH-UHFFFAOYSA-N methyl 2-[4-(4-fluorophenyl)piperazin-1-yl]-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-3-[3-(trifluoromethyl)phenyl]-4h-quinazoline-6-carboxylate Chemical compound C=1C=CC(C(F)(F)F)=CC=1N1C(CC(=O)OC(C)(C)C)C2=CC(C(=O)OC)=CC=C2N=C1N(CC1)CCN1C1=CC=C(F)C=C1 RHVXRSVSXRBAAH-UHFFFAOYSA-N 0.000 description 1
- KPPKMZWXNRCMBX-UHFFFAOYSA-N methyl 2-[6-cyano-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=CC=C(C#N)C=C2C(CC(=O)OC)N(C=2C=C(C=CC=2)C(F)(F)F)C=1N(CC1)CCN1C1=CC=C(F)C=C1 KPPKMZWXNRCMBX-UHFFFAOYSA-N 0.000 description 1
- NCMUTIGYDQLGRB-UHFFFAOYSA-N methyl 2-[7-cyano-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=CC(C#N)=CC=C2C(CC(=O)OC)N(C=2C=C(C=CC=2)C(F)(F)F)C=1N(CC1)CCN1C1=CC=C(F)C=C1 NCMUTIGYDQLGRB-UHFFFAOYSA-N 0.000 description 1
- SNYITORSQYEDKV-UHFFFAOYSA-N methyl 2-[8-fluoro-2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]-3-(2-methoxy-5-methylphenyl)-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C)C=2)OC)C=1N(CC1)CCN1C1=CC=C(F)C(C)=C1 SNYITORSQYEDKV-UHFFFAOYSA-N 0.000 description 1
- CUCYIGYTDGGHIU-UHFFFAOYSA-N methyl 2-[8-fluoro-2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=C(F)C(C)=C1 CUCYIGYTDGGHIU-UHFFFAOYSA-N 0.000 description 1
- JVOIWCACEFPZII-VOTSOKGWSA-N methyl 2-amino-3-[(e)-3-methoxy-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)\C=C\C1=CC=CC(C(=O)OC)=C1N JVOIWCACEFPZII-VOTSOKGWSA-N 0.000 description 1
- FGSIUBWPZRBMOC-UHFFFAOYSA-N methyl 2-amino-3-bromobenzoate Chemical compound COC(=O)C1=CC=CC(Br)=C1N FGSIUBWPZRBMOC-UHFFFAOYSA-N 0.000 description 1
- CTSAXXHOGZNKJR-UHFFFAOYSA-N methyl 2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)CC(=O)OC CTSAXXHOGZNKJR-UHFFFAOYSA-N 0.000 description 1
- DYQKJVGXBQOJNM-UHFFFAOYSA-N methyl 3-(2-amino-6-fluorophenyl)prop-2-enoate Chemical compound COC(=O)C=CC1=C(N)C=CC=C1F DYQKJVGXBQOJNM-UHFFFAOYSA-N 0.000 description 1
- WRDFFTGRCFAUNR-XTQSDGFTSA-N methyl 3-[(e)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-4-[(triphenyl-$l^{5}-phosphanylidene)amino]benzoate Chemical compound CC(C)(C)OC(=O)/C=C/C1=CC(C(=O)OC)=CC=C1N=P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WRDFFTGRCFAUNR-XTQSDGFTSA-N 0.000 description 1
- VSAXBDHAQCVJPP-SOFGYWHQSA-N methyl 4-amino-3-[(e)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)C1=CC=C(N)C(\C=C\C(=O)OC(C)(C)C)=C1 VSAXBDHAQCVJPP-SOFGYWHQSA-N 0.000 description 1
- QYMOTVAZPUDFFL-GQCTYLIASA-N methyl 4-amino-3-[(e)-3-methoxy-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)\C=C\C1=CC(C(=O)OC)=CC=C1N QYMOTVAZPUDFFL-GQCTYLIASA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000001117 sulphuric acid Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WRRXHLGOGAHSOJ-UHFFFAOYSA-N tert-butyl 2-[6-carbamoyl-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=CC=C(C(N)=O)C=C2C(CC(=O)OC(C)(C)C)N(C=2C=C(C=CC=2)C(F)(F)F)C=1N(CC1)CCN1C1=CC=C(F)C=C1 WRRXHLGOGAHSOJ-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- CMMXCVYESRODNH-UHFFFAOYSA-N trichloroepoxyethane Chemical class ClC1OC1(Cl)Cl CMMXCVYESRODNH-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Definitions
- Reissue application Ser. No. 15/955,254 is a continuation of Reissue application Ser. No. 14/682,512 and an application for reissue of application Ser. No. 10/832,109 (U.S. Pat. No. 7,196,086).
- Reissue application Ser. No. 14/682,512 is an application for reissue of application Ser. No. 10/832,109 (U.S. Pat. No. 7,196,086).
- Reissue application Ser. No. 14/682,512 matured into Reissue U.S. Pat. No. RE46,791 on Apr. 17, 2018.
- the invention relates to substituted dihydroquinazolines and to processes for their preparation and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegalo viruses.
- One object of the present invention is therefore to provide novel compounds having the same or improved antiviral effect for the treatment of viral infective diseases in humans and animals.
- the present invention provides compounds of the formula
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds mentioned below as embodiment(s) and their salts, solvates and solvates of the salts, unless the compounds below, embraced by formula (I), are already salts, solvates and solvates of the salts.
- the compounds according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers).
- the invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof.
- the stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
- the compounds according to the invention may exist in tautomeric forms, the present invention embraces all such tautomeric forms.
- Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention.
- the invention also embraces salts which are per se not suitable for pharmaceutical applications but can be used, for example, for isolating or purifying the compounds according to the invention.
- Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
- hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid,
- Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- customary bases such as, by way of example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammoni
- Solvates refer for the purposes of the invention to those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which the coordination takes place with water.
- Alkyl per se and “alk” and “alkyl” in alkoxy, alkylamino, alkylcarbonyl, alkylsulphonyl, alkylaminosulphonyl and alkoxycarbonyl are a straight-chain or branched alkyl radical having generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
- Alkoxy is, by way of example and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
- Alkylamino is an alkylamino radical having one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propyl-amino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
- C 1 —C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon
- Alkylsulphonyl is, by way of example and preferably, methylsulphonyl, ethylsulphonyl, n-propyl-sulphonyl, iso-propylsulphonyl, tert-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl.
- Alkylaminosulphonyl is an alkylaminosulphonyl radical having one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl, tert-butylaminosulphonyl, n-pentylaminosulphonyl, n-hexyl-aminosulphonyl, N-N-dimethylaminosulphonyl, N-N-diethyl-aminosulphonyl, N-ethyl-N-methylaminosulphonyl, N-methyl-N-n-propylamiinosulphonyl N-methyl-N-n-propylaminosulphonyl, N-isopropyl-N-n-propyl-aminosulphonyl, N-tert-butyl-N-methyl
- C 1 —C 3 -alkylaminosulphonyl is, for example, a monoalkylaminosulphonyl radical having 1 to 3 carbon atoms or a dialkylaminosulphonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
- Alkylcarbonyl is, by way of example and preferably, acetyl and propanoyl.
- Alkoxycarbonyl is, by way of example and preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy-carbonyl.
- Aryl is a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms; by way of example and preferably phenyl, naphthyl and phenanthrenyl.
- Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
- a symbol * on a carbon atoms means that the compound, with respect to the configuration at this carbon atom, is present in enantiomerically pure form which, for the purposes of the present invention, is to be understood as meaning an enantiomeric excess of more than 90% (>90% ee).
- R 3 represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.
- R 1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring
- R 3 represents trifluoromethyl, chlorine or methyl
- R 3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R 1 .
- R 1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring
- R 3 represents trifluoromethyl
- R 3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R 1 .
- radical definitions given in the respective combinations or preferred combinations of radicals are, independently of the combinations of radicals given in each case, also replaced by radical definitions of other combinations.
- the invention furthermore provides a process for preparing the compounds of the formula (I), which comprises reacting compounds of the formula
- the reaction is generally carried out using bases in inert solvents, preferably in a temperature range of from room temperature to the reflux temperature of the solvent, at atmospheric pressure.
- Suitable bases are, for example, alkali metal hydroxides, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates, such as caesium carbonate, sodium carbonate or potassium carbonate, if appropriate in aqueous solution; preference is given to sodium hydroxide in water.
- alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide
- alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate
- Inert solvents are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of solvents; preference is given to dioxane or tetrahydrofuran.
- ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
- alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of solvents; preference is given to dioxane or tetrahydrofuran.
- reaction is generally carried out using acids in inert solvents, preferably in a temperature range of from 0° C. to 40° C., at atmospheric pressure.
- suitable acids are hydrogen chloride in dioxane, hydrogen bromide in acetic acid or trifluoroacetic acid in methylene chloride.
- Both steps of the reaction are generally carried out in inert solvents, preferably in a temperature range of from room temperature to 100° C., at atmospheric pressure.
- silica gel is added to the reaction mixture.
- the reaction is preferably carried out with work-up between the first and the second step.
- Suitable inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or ethyl acetate, or mixtures of solvents; preference is given to methylene chloride.
- halogenated hydrocarbons such as methylene
- the compounds of the formula (IV) are known or can be synthesized by known processes from the corresponding starting materials.
- the compounds of the formula (V) are known or can be synthesized by known processes from the corresponding starting materials, for example by a Buchwald-Hartwig reaction according to the synthesis scheme below (review in: C. G. Frost, P. Mendonca, J. Chem. Soc., Perkin Trans I, 1998, 2615-2623):
- the starting materials required for this purpose are known or can be synthesized by known processes from the corresponding starting materials.
- the reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of from room temperature to 50° C., at atmospheric pressure.
- Suitable inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine; preference is given to acetonitrile.
- ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
- hydrocarbons such as benzene, xylene, toluene, hexane,
- Suitable bases are, for example, alkali metal and alkaline earth metal carbonates, such as caesium carbonate, sodium carbonate or potassium carbonate, or amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine; preference is given to triethylamine.
- alkali metal and alkaline earth metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate
- amines such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine; preference is given to triethylamine.
- the compounds of the formula (VI) are known or can be synthesized by known processes from the corresponding starting materials, for example by a Heck reaction or a Wittig-Homer Wittig-Horner reaction, according to the synthesis schemes below:
- the starting materials required for this purpose are known or can be synthesized by known processes from the corresponding starting materials.
- the compounds of the general formula (I) according to the invention show a surprising range of effects which could not have been predicted. They show an antiviral effect on representatives of the group of the Herpes viridae (Herpes viruses), especially on cytomegalo viruses (CMV), in particular, on human cytomegalovirus (HCMV).
- Herpes viruses Herpes viridae
- CMV cytomegalo viruses
- HCMV human cytomegalovirus
- the present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, especially of infections with viruses, in particular the viruses mentioned above, and the infective diseases caused by these infections.
- a viral infection is to be understood as including both an infection with a virus and a disease caused by an infection with a virus.
- the present invention also provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
- the present invention also provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
- the compounds according to the invention are preferably used for preparing medicaments suitable for the prophylaxis and/or treatment of infections with a representative of the group of the Herpes viridae, in particular a cytomegalovirus, in particular the human cytomegalovirus.
- the present invention also provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an antivirally effective amount of the compounds according to the invention.
- the present invention also provides medicaments comprising at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and/or prophylaxis of the disorders mentioned above.
- Active compounds suitable for combinations are, by way of example and preferably: antiviral active compounds, such as gancyclovir or acyclovir.
- the compounds according to the invention can act systemically and/or locally.
- they can be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as implant or stent.
- Suitable for oral administration are known administration forms which deliver the compounds according to the invention rapidly and/or in modified form and which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example tablets provided with enteric coatings or coatings which dissolve slowly or are insoluble and which control the release of the compound according to the invention), tablets which disintegrate rapidly in the oral cavity and/or films/wafers, films/lyophylisates, capsules (for example Hart or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
- tablets uncoated or coated tablets, for example tablets provided with enteric coatings or coatings which dissolve slowly or are insoluble and which control the release of the compound according to the invention
- tablets which disintegrate rapidly in the oral cavity and/or films/wafers, films/lyophylisates capsules (for example Hart or soft gelatin capsule
- Parenteral administration can take place with avoidance of an adsorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
- Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- Examples suitable for other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops/solutions/sprays; tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes, foams, dusting powders, implants or stents.
- pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
- nasal drops/solutions/sprays tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, cream
- the compounds according to the invention can be converted into the stated administration forms.
- auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxides) and flavour- and/or odour-masking agents.
- carriers for example microcrystalline cellulose, lactose, mannitol
- solvents for example liquid polyethylene glycols
- emulsifiers and dispersants or wetting agents for example sodium dodecyl sulphate, polyoxysorbitan oleate
- binders for example polyvinylpyrrolidone
- synthetic and natural polymers for example albumin
- stabilizers
- the present invention furthermore provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable auxiliaries, and their use for the purposes mentioned above.
- intravenous administration amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/kg, of body weight to achieve effective results, and the dosage on oral administration is about 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
- Method 1 (analytical HPLC): column: Kromasil C18 60 mm ⁇ 2 mm; temperature: 30° C.; flow rate: 0.75 ml/min; mobile phase A: 0.005 M HClO 4 , mobile phase B: acetonitrile; gradient: ⁇ 0.5 min 98% A, ⁇ 4.5 min 10% A, ⁇ 6.5 min 10% A.
- Method 2 (preparative HPLC): column: GromSil C18, 250 mm ⁇ 30 mm; flow rate: 50 ml/min; time per run: 38 min; detection: 210 nm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% B (3 min)->90% B (31 min)->90% B (34 min)->10% B (34.01 min).
- Method 3 column: GromSil 120 ODS-4 HE, 50 mm ⁇ 2.0 mm, 3 ⁇ m; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min; UV detection: 208-400 nm.
- Method 4 (preparative HPLC, separation of enantiomers, carboxylic acids): column: packing chiral silica gel selector KBD 8361 (420 mm ⁇ 100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide) poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound is dissolved in methyl tert-butyl ether/ethyl acetate (9:1).
- Method 5 (preparative HPLC): column: GromSil C18, 250 mm ⁇ 30 mm; flow rate: 50 ml/min; time per run: 38 min; detection: 210 nm; mobile phase A: water with 0.1% formic acid, mobile phase B: acetonitrile; gradient: 10% B (3 min)->90% B (31 min)->90% B (34 min)->10% B (34.01 min).
- Method 6 (analytical HPLC): instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; mobile phase A: 5 ml of HClO 4 /l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; flow rate: 0.75 ml/min; temp.: 30° C.; detection: UV 210 nm.
- Method 7 instrument: Micromass Platform LCZ with HPLC Agilent series 1100; column: GromSIL120 ODS-4 HE, 50 mm ⁇ 2.0 mm, 3 ⁇ m; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
- Method 8 instrument: Micromass Platform LCZ, HP 1100; column: Symmetry C18, 50 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: acetonitrile+0.1% formic acid, mobile phase B: water+0.1% formic acid; gradient: 0.0 min 10% A ⁇ 4.0 min 90% A ⁇ 6.0 min 90% A; oven: 40° C.; flow rate: 0.5 ml/min; UV detection: 208-400 nm.
- Method 9 MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm ⁇ 4.6 mm; mobile phase A: water+500 ⁇ l of 50% strength formic acid/l, mobile phase B: acetonitrile+500 ⁇ l of 50% strength formic acid/l; gradient: 0.0 min 10% B ⁇ 3.0 min 95% B ⁇ 4.0 min 95% B; oven: 35° C.; flow rate: 0.0 min 1.0 ml/min ⁇ 3.0 min 3.0 ml/min ⁇ 4.0 min 3.0 ml/min; UV detection: 210 nm.
- Method 10 MS instrument: Micromass ZQ; HPLC instrument: HP 1100 Series; UV DAD; column: Grom-Sil 120 ODS-4 HE 50 mm ⁇ 2 mm, 3.0 ⁇ m; mobile phase A: water+500 ⁇ l of 50% strength formic acid/l, mobile phase B: acetonitrile+500 ⁇ l of 50% strength formic acid/l; gradient: 0.0 min 0% B ⁇ 2.9 min 70% B ⁇ 3.1 min 90% B ⁇ 4.5 min 90% B; oven: 50° C.; flow rate: 0.8 ml/min; WV UV detection: 210 nm.
- Method 11 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 8361 (250 mm ⁇ 20 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether+5% ethyl acetate; flow rate: 25 ml/min.
- Method 12 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 5326 (250 mm ⁇ 20 mm) based on the selector poly(N-methacryloyl-L-leucine-dicyclopropylmethylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether+5% ethyl acetate; flow rate: 25 ml/min.
- Method 13 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 8361 (250 mm ⁇ 20 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 25 ml/min.
- Method 14 (preparative HPLC, separation of enantiomers, esters): column: packing chiral silica gel selector KBD 8361 (420 mm ⁇ 100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: isohexane/ethyl acetate 85/15 v/v; flow rate: 100 ml/min; the compound is dissolved in isohexane/ethyl acetate (85:15).
- Method 15 (preparative HPLC, separation of enantiomers, esters): column: packing chiral silica gel selector KBD 8361 (420 mm ⁇ 100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound is dissolved in methyl tert-butyl ether.
- Method 16 instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; column: Grom-SIL120 ODS-4 HE, 50 mm ⁇ 2.0 mm, 3 ⁇ m; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 4.5 min 10% A; oven: 55° C.; flow rate: 0.8 m/min; UV detection: 208-400 nm.
- Method 17 MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50 mm ⁇ 2 mm, 3.0 ⁇ m; mobile phase A: water+500 ⁇ l of 50% strength formic acid/l, mobile phase B: acetonitrile+500 ⁇ l of 50% strength formic acid/l; gradient: 0.0 min 0% B ⁇ 0.2 min 0% B ⁇ 2.9 min 70% B ⁇ 3.1 min 90% B ⁇ 4.5 min 90% B; oven: 45° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
- the organic phase is separated off and the aqueous phase is re-extracted with ethyl acetate.
- the organic phases are combined, washed once with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is concentrated to about half of its original volume.
- Activated carbon corresponding to 1% of the weight of the nitro compound is then added, and the mixture is heated under reflux for 30 minutes (the colour of the solution changes). The activated carbon is filtered off and the solvent is removed.
- the residue obtained is an oil which, on drying at RT under high vacuum, forms crystals. Without further purification, the product is directly used for the next step.
- the reaction flask is thoroughly dried by heating under high vacuum and vented with argon.
- 1.0 equivalent of the bromoaryl compound and 6.0 equivalents of piperazine in absolute toluene are initially charged in the flask (0.2-0.3M solution of the bromo compound).
- 0.01 equivalent of tris(dibenzylideneacetone)dipalladium and 0.03 equivalent of BINAP are then added.
- the reaction mixture is stirred under reflux for 16 h.
- the mixture is then extracted once with water, the organic phase is extracted twice with 1N hydrochloric acid and the aqueous phase is adjusted to pH 8 using 1N aqueous sodium hydroxide solution and extracted three times with dichloromethane.
- the combined organic phases are dried over sodium sulphate and filtered, the solvent is removed under reduced pressure and the product is dried under high vacuum overnight.
- the NMR shows the presence of a varying proportion of non-cyclized reaction product.
- the mixture of cyclized and non-cyclized product is taken up in dioxane, a spatula tip of silica gel is added and the mixture is stirred under reflux for 30 min to 16 h. The silica gel is filtered off and the solution is used for further reactions.
- Example 18A 700 mg (1.78 mmol) of methyl (2E)-3- ⁇ 3-fluoro-2-[( ⁇ [2-methoxy-5-(trifluoromethyl)phenyl]-imino ⁇ methylene)amino]phenyl ⁇ -2-propenoate (Example 18A), 352 mg (1.78 mmol) of 1-(3,4-difluorophenyl)piperazine (Example 16A) and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is then purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
- Example 18A 100 mg (0.25 mmol) of methyl (2E)-3- ⁇ 3-fluoro-2-[( ⁇ [2-methoxy-5-(trifluoromethyl)phenyl]-imino ⁇ methylene)amino]phenyl ⁇ -2-propenoate (Example 18A), 45.7 mg (0.25 mmol) of 1-(3-fluorophenyl)piperazine (Example 15A) and a spatula tip of silica gel are stirred in 15 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
- This compound is obtained as enantiomer A by separating the racemate from Example 30A chromatographically according to Method 15 in to into the enantiomers. Starting with 231 g of racemate, 120 g of the target product, which is directly reacted further, are obtained.
- the compound is obtained as enantiomer A by separating the racemate from Example 31A chromatographically according to Method 15 into the enantiomers. Starting with 231 g of racemate, 111 g (48% of theory) of the target product are obtained.
- Examples 50A to 112A 111A of Table 1 can be prepared from the corresponding starting materials using the general procedures [A] to [G].
- the target product is obtained by reacting the enantiomerically pure ester from Example 43A according to the general procedure [H]. Starting with 111 g (0.19 mol) of ester, 69 g (63% of theory) of target product are obtained.
- the target product is obtained by reacting the enantiomerically pure ester from Example 42A according to the general procedure [11] [H]. Starting with 120 g (0.21 mol) of ester, 96 g (81% of theory) of target product are obtained.
- Example 34A methyl ⁇ 8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl ⁇ acetate
- Example 34A methyl ⁇ 8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl ⁇ acetate
- Examples 26 to 34 and 36 to 89 of Table 2 can be prepared from the corresponding starting materials using the general procedures [A] to [H], and Example 35 can be prepared as described below in Table 2.
- Example 89 80 mg (0.14 mmol) of the methyl ether (Example 89) are dissolved in 2 ml of dichloromethane, and 0.41 mmol of a 1M solution of boron tribromide in dichloromethane is added at 0° C. The mixture is stirred at room temperature for 16 hours, a further 0.82 mmol of the boron tribromide solution is added, followed by a further 1.23 mmol after 24 hours. The reaction mixture is stirred at room temperature for 24 hours and then poured onto ice, and 5 ml of a 1N aqueous hydrochloric acid solution are added. The mixture is extracted with 25 ml of ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, concentrated and purified by preparative HPLC. This gives 50 mg (63% of theory) of product.
- test compounds are employed as 50 millimolar (mM) solutions in dimethyl sulphoxide (DMSO).
- DMSO dimethyl sulphoxide
- Ganciclovir®, Foscarnet® and Cidofovir® are used as reference compounds.
- 1:2 dilutions are carried out with 50 ⁇ l portions of medium up to row 11 of the 96-well plate.
- the wells in rows 1 and 12 each contain 50 ⁇ l of medium.
- the wells are then fixed and stained by adding a mixture of formalin and Giemsa's dye (30 minutes), washed with double-distilled water and dried in a drying oven at 50° C.
- the plates are then assessed visually using an overhead microscope (Plaque Multiplier from Technomara).
- EC 50 substance concentration in ⁇ M which inhibits the CPE (cytopathic effect) by 50% compared with the untreated virus control;
- SI selection index
- mice 3-4-week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID beige, are purchased from commercial breeders (Taconic M+B, Jackson USA). The animals are housed under sterile conditions (including bedding and feed) in isolators.
- HCMV Human cytomegalovirus
- NHDF cells human embryonic prepuce fibroblasts
- MEM minimal essential medium
- FCS fetal calf serum
- DMSO fetal calf serum
- PBS phosphate-buffered saline
- the infected sponges are incubated with 25 ⁇ l of PBS/0.1% BSA/1 mM DTT with 5 ng/ ⁇ l basic fibroblast growth factor (bFGF).
- the immunodeficient mice are anaesthetized with Avertin or a ketamine/xylazine/azepromazine mixture, the fur on the back is removed using a shaver, the epidermis is opened 1-2 cm, unstressed and the moist sponges are transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 6 hours after the transplantation, the mice can be treated for the first time (on the day of the operation, there is one treatment).
- mice are treated with substance orally three times a day (7.00 h and 14.00 h and 19.00 h), two times a day (8.00 h and 18.00 h) or once a day (14.00 h).
- the daily dose is, for example 3 or 10 or 30 or 60 or 100 mg/kg of body weight, the volume administered is 10 ml/kg of body weight.
- the substances are formulated in the form of a 0.5% strength Tylose suspension with 2% DMSO or a 0.5% strength Tylose suspension. 9 days after transplantation and 16 hours after the last administration of substance, the animals are painlessly sacrificed and the sponge is removed.
- the virus-infected cells are released from the sponge by collagenase digestion (330 U/1.5 ml) and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO at ⁇ 140° C. Evaluation takes place after serial ten-fold dilutions of the virus-infected cells by determining the titer on 24-well plates of confluent NHDF cells after vital staining with Neutral Red. The number of infected cells or infectious virus particles (infectious centre assay) after the substance treatment compared with the placebo-treated control is determined.
- CYP3A4 To investigate the mechanism-based (irreversible) inhibition of CYP3A4, different concentrations of the test substance are incubated with human liver microsomes (2 mg/ml of microsomal protein) in potassium phosphate buffer pH 7.4 with addition of an NADPH-generating system (NADP+, glucose 6-phosphate, glucose 6-phosphate dehydrogenase) at 37° C. At various points of time, 2 aliquots are taken from the incubation.
- NADPH-generating system NADP+, glucose 6-phosphate, glucose 6-phosphate dehydrogenase
- the first aliquot is incubated 1:50 in a new incubation solution (phosphate buffer, NADPH-generating system and 10 ⁇ M of Midazolam) at 37° C. for a further 10 min.
- the incubation is then stopped using acetonitrile on ice, the protein is pelleted in a centrifuge at 15 000 g and the supernatant is analysed for formation of 1′-hydroxyimidazolam using standard HPLC/MS methods.
- the second aliquot is stopped using acetonitrile on ice and analysed for remaining test substance using HPLC/UV/MS.
- the two sets of analytical data are determined for irreversible-inhibition-typical parameters (k inact , K i and partition ratio r), and using these data, the test substance is evaluated (cf. A. Madan, et al., in A. D. Rodrigues (ed.) “Drug-Drug Interaction” in “Drugs and the Pharmaceutical Science”, Vol. 116, ISBN 0-8247-0283.2, Marcel Dekker Inc., New York, 2002.).
- the compounds of the invention can be converted into pharmaceutical preparations in the following ways:
- Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
- lactose monohydrate
- corn starch 50 mg
- PVP 25 polyvinylpyrrolidone
- the mixture of active ingredient, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water.
- the granules are then dried and mixed with the magnesium stearate for 5 min.
- This mixture is compressed using a conventional tablet press (see above for format of the tablet).
- a guideline for the compressive force used for the compression is 15 kN.
- 10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound of the invention.
- Rhodigel is suspended in ethanol, and the active ingredient is added to the suspension.
- the water is added while stirring.
- the mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.
- Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
- the solution is sterilized by filtration (pore diameter 0.22 ⁇ m) and dispensed under aseptic conditions into heat-sterilized infusion bottles. The latter are closed with infusion stoppers and trimmed caps.
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Abstract
The invention relates to substituted dihydroquinazolines and to processes for their preparation and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegalo viruses.
Description
More than one reissue application has been filed for the reissue of U.S. Pat. No. 7,196,086. The reissue applications are Application Serial No. (the present application), application Ser. No. 15/955,254 (pending on the filing date of this application and abandoned on Nov. 3, 2020) and application Ser. No. 14/682,512 (now U.S. RE46,791), all of which are reissues of U.S. Pat. No. 7,196,086.
This application is a continuation of Reissue application Ser. No. 15/955,254, which was pending on the filing date of this application. This application is an application for reissue of application Ser. No. 10/832,109, which was filed Apr. 26, 2004 and issued on Mar. 27, 2007 as U.S. Pat. No. 7,196,086. Reissue application Ser. No. 15/955,254 is a continuation of Reissue application Ser. No. 14/682,512 and an application for reissue of application Ser. No. 10/832,109 (U.S. Pat. No. 7,196,086). Reissue application Ser. No. 14/682,512 is an application for reissue of application Ser. No. 10/832,109 (U.S. Pat. No. 7,196,086). Reissue application Ser. No. 14/682,512 matured into Reissue U.S. Pat. No. RE46,791 on Apr. 17, 2018.
The invention relates to substituted dihydroquinazolines and to processes for their preparation and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegalo viruses.
The synthesis of dihydroquinazolines is described in Saito T., et al. Tetrahedron Lett., 1996, 37, 209-212 and in Wang F., et al. Tetrahedron Lett., 1997, 38, 8651-8654.
Although agents with antiviral activity and a different structure are available on the market, it is always possible for resistance to develop. Novel agents for an effective therapy are therefore desirable.
One object of the present invention is therefore to provide novel compounds having the same or improved antiviral effect for the treatment of viral infective diseases in humans and animals.
It has been found, surprisingly, that the substituted dihydroquinazolines described in the present invention have antiviral effect.
The present invention provides compounds of the formula
- Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and nitro,
- where alkyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,
- or two of the substituents on the aryl radical together with the carbon atoms to which they are attached form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring, and any third substituent present is selected independently from the group mentioned,
- R1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
- R2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
- R3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl
or
one of the radicals R1, R2 and R3 represents hydrogen, alkyl, alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two together with the carbon atoms to which they are attached form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring, - R4 represents hydrogen or alkyl,
- R5 represents hydrogen or alkyl
or
the radicals R4 and R5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups, - R6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
- R7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro
and - R8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro, and their salts, their solvates and the solvates of their salts.
Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds mentioned below as embodiment(s) and their salts, solvates and solvates of the salts, unless the compounds below, embraced by formula (I), are already salts, solvates and solvates of the salts.
The compounds according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
If the compounds according to the invention may exist in tautomeric forms, the present invention embraces all such tautomeric forms.
Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, the invention also embraces salts which are per se not suitable for pharmaceutical applications but can be used, for example, for isolating or purifying the compounds according to the invention.
Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
Solvates refer for the purposes of the invention to those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which the coordination takes place with water.
For the purposes of the present invention, unless specified otherwise, the substituents have the following meanings:
Alkyl per se and “alk” and “alkyl” in alkoxy, alkylamino, alkylcarbonyl, alkylsulphonyl, alkylaminosulphonyl and alkoxycarbonyl are a straight-chain or branched alkyl radical having generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
Alkoxy is, by way of example and preferably, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkylamino is an alkylamino radical having one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propyl-amino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. C1—C3-alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkylsulphonyl is, by way of example and preferably, methylsulphonyl, ethylsulphonyl, n-propyl-sulphonyl, iso-propylsulphonyl, tert-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl.
Alkylaminosulphonyl is an alkylaminosulphonyl radical having one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl, tert-butylaminosulphonyl, n-pentylaminosulphonyl, n-hexyl-aminosulphonyl, N-N-dimethylaminosulphonyl, N-N-diethyl-aminosulphonyl, N-ethyl-N-methylaminosulphonyl, N-methyl-N-n-propylamiinosulphonyl N-methyl-N-n-propylaminosulphonyl, N-isopropyl-N-n-propyl-aminosulphonyl, N-tert-butyl-N-methylaminosulphonyl, N-ethyl-N-n-pentyl-aminosulphonyl and N-n-hexyl-N-methylaminosulphonyl. C1—C3-alkylaminosulphonyl is, for example, a monoalkylaminosulphonyl radical having 1 to 3 carbon atoms or a dialkylaminosulphonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
Alkylcarbonyl is, by way of example and preferably, acetyl and propanoyl.
Alkoxycarbonyl is, by way of example and preferably, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy-carbonyl.
Aryl is a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms; by way of example and preferably phenyl, naphthyl and phenanthrenyl.
Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
A symbol * on a carbon atoms means that the compound, with respect to the configuration at this carbon atom, is present in enantiomerically pure form which, for the purposes of the present invention, is to be understood as meaning an enantiomeric excess of more than 90% (>90% ee).
Preference is given to those compounds of the formula (I) in which
- Ar represents phenyl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of C1—C6-alkyl, C1—C6-alkoxy, carboxyl, C1—C6-alkylcarbonyl, C1—C6-alkoxycarbonyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C1—C6-alkylamino and nitro,
- or two of the substituents on the phenyl radical together with the carbon atoms to which they are attached form a 1,3-dioxolane and any third substituent present is selected independently from the group mentioned,
- R1 represents hydrogen, C1—C3-alkyl, C1—C3-alkoxy, C1—C3-alkylthio, fluorine or chlorine,
- R2 represents hydrogen, C1—C3-alkyl, C1—C3-alkoxy, C1—C3-alkylthio, fluorine or chlorine,
- R3 represents C1—C4-alkyl, cyano, fluorine, chlorine, nitro, trifluoromethyl or C1—C3-alkylsulphonyl,
or
one of the radicals R1, R2 and R3 represents hydrogen, C1—C3-alkyl, C1—C3-alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two together with the carbon atoms to which they are attached form a cyclopentane ring or a cyclohexane ring, - R4 represents hydrogen or methyl,
- R5 represents hydrogen,
- R6 represents C1—C3-alkyl, C1—C3-alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,
- R7 represents hydrogen, C1—C3-alkyl, C1—C3-alkoxy, fluorine, chlorine, cyano or hydroxyl
and - R8 represents hydrogen, C1—C3-alkyl, C1—C3-alkoxy, fluorine, chlorine, cyano or hydroxyl.
Among these, particular preference is given to those compounds of the formula (I), in which
- Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine,
- R1 represents hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,
- R2 represents hydrogen,
- R3 represents methyl, isopropyl, tert-butyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
- R4 represents hydrogen,
- R5 represents hydrogen,
- R6 represents aminocarbonyl, fluorine, chlorine, cyano or hydroxyl,
- R7 represents hydrogen
and - R8 represents hydrogen, fluorine or chlorine.
Among these, particular preference is also given to those compounds of the formula (I), in which
- Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine,-
- R1 represents hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,
- R2 represents hydrogen,
- R3 represents methyl, tert-butyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
- R4 represents hydrogen,
- R5 represents hydrogen,
- R6 represents aminocarbonyl, fluorine, chlorine, cyano or hydroxyl,
- R7 represents hydrogen
and - R8 represents hydrogen, fluorine or chlorine.
Among these, very particular preference is given to those compounds of the formula (I), in which
- Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine,
- R1 represents hydrogen or methoxy,
- R2 represents hydrogen,
- R3 represents methyl, tert-butyl, chlorine or trifluoromethyl,
- R4 represents hydrogen,
- R5 represents hydrogen,
- R6 represents aminocarbonyl or fluorine,
- R7 represents hydrogen
and - R8 represents hydrogen or fluorine.
Preference is also given to those compounds of the formula (I), in which R1 represents hydrogen, methyl, methoxy or fluorine.
Among these, particular preference is given to those compounds of the formula (I), in which R1 represents methoxy.
Preference is also given to those compounds of the formula (I) in which R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring. For the purposes of the present invention, the point of attachment of the phenyl ring substituted by radicals R1, R2 and R3 is to be understood as meaning the carbon atom of the phenyl ring which, according to formula (I), is attached to one of the two nitrogen atoms of the dihydroquinazoline.
Particular preference is given to those compounds of the formula (I), in which R1 represents methoxy and R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring.
Preference is also given to those compounds of the formula (I) in which R2 represents hydrogen.
Preference is also given to those compounds of the formula (I) in which R3 represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.
Among these, particular preference is given to those compounds of the formula (D) (I) in which R3 represents trifluoromethyl, chlorine or methyl.
Among these, very particular preference is given to those compounds of the formula (I) in which R3 represents trifluoromethyl.
Preference is also given to those compounds of the formula (I) in which R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring and R3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R1.
Particular preference is given to those compounds of the formula (I) in which R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring, R3 represents trifluoromethyl, chlorine or methyl and R3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R1.
Among these, particular preference is given to those compounds of the formula (I) in which R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring, R3 represents trifluoromethyl and R3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R1.
Preference is also given to those compounds of the formula (I) in which R4 and R5 represent hydrogen.
Preference is also given to those compounds of the formula (I) in which R6 represents fluorine.
Particular preference is given to those compounds of the formula (I) in which R6 represents fluorine and R6 is, as described in formula
Preference is also given to those compounds of the formula (I) in which R7 represents hydrogen.
Among these, particular preference is given to those compounds of the formula (I) in which R8 represents hydrogen, methyl or fluorine.
Among these, very particular preference is given to those compounds of the formula (I) in which R8 represents hydrogen.
Preference is also given to those compounds of the formula (I) in which Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine.
The particular radical definitions given in the respective combinations or preferred combinations of radicals are, independently of the combinations of radicals given in each case, also replaced by radical definitions of other combinations.
Very particular preference is given to combinations of two or more of the preferred ranges mentioned above.
The invention furthermore provides a process for preparing the compounds of the formula (I), which comprises reacting compounds of the formula
- Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above and
- R9 represents alkyl, preferably methyl or ethyl or tert-butyl, with bases or acids.
In the case of methyl and ethyl, the reaction is generally carried out using bases in inert solvents, preferably in a temperature range of from room temperature to the reflux temperature of the solvent, at atmospheric pressure.
Suitable bases are, for example, alkali metal hydroxides, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates, such as caesium carbonate, sodium carbonate or potassium carbonate, if appropriate in aqueous solution; preference is given to sodium hydroxide in water.
Inert solvents are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of solvents; preference is given to dioxane or tetrahydrofuran.
In the case of tert-butyl, the reaction is generally carried out using acids in inert solvents, preferably in a temperature range of from 0° C. to 40° C., at atmospheric pressure.
Here, suitable acids are hydrogen chloride in dioxane, hydrogen bromide in acetic acid or trifluoroacetic acid in methylene chloride.
The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula
in which
R6, R7, R8 and R9 are as defined above
in a two-step reaction initially with compounds of the formula
- R1, R2 and R3 are as defined above
and then with compounds of the formula
- Ar, R4 and R5 are as defined above.
Both steps of the reaction are generally carried out in inert solvents, preferably in a temperature range of from room temperature to 100° C., at atmospheric pressure. In the second step, if appropriate, silica gel is added to the reaction mixture. The reaction is preferably carried out with work-up between the first and the second step.
Suitable inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or ethyl acetate, or mixtures of solvents; preference is given to methylene chloride.
The compounds of the formula (IV) are known or can be synthesized by known processes from the corresponding starting materials.
The compounds of the formula (V) are known or can be synthesized by known processes from the corresponding starting materials, for example by a Buchwald-Hartwig reaction according to the synthesis scheme below (review in: C. G. Frost, P. Mendonca, J. Chem. Soc., Perkin Trans I, 1998, 2615-2623):
The starting materials required for this purpose are known or can be synthesized by known processes from the corresponding starting materials.
The compounds of the formula (M) (III) are known or can be prepared by reacting compounds of the formula
- R6, R7, R8 and R9 are as defined above
with triphenylphosphine and carbon tetrachloride.
The reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of from room temperature to 50° C., at atmospheric pressure.
Suitable inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine; preference is given to acetonitrile.
Suitable bases are, for example, alkali metal and alkaline earth metal carbonates, such as caesium carbonate, sodium carbonate or potassium carbonate, or amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine; preference is given to triethylamine.
The compounds of the formula (VI) are known or can be synthesized by known processes from the corresponding starting materials, for example by a Heck reaction or a Wittig-Homer Wittig-Horner reaction, according to the synthesis schemes below:
The starting materials required for this purpose are known or can be synthesized by known processes from the corresponding starting materials.
The preparation of the compounds according to the invention can be illustrated by the synthesis scheme below.
The compounds of the general formula (I) according to the invention show a surprising range of effects which could not have been predicted. They show an antiviral effect on representatives of the group of the Herpes viridae (Herpes viruses), especially on cytomegalo viruses (CMV), in particular, on human cytomegalovirus (HCMV).
Areas of indication which may be mentioned by way of example are:
- 1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
- 2) Treatment and prophylaxis of cytomegalovirus infections in bone-marrow and organ transplantations which develop often life-threatening HCMV pneumonitis or encephalitis, and gastrointestinal and systemic HCMV infections.
- 3) Treatment and prophylaxis of HCMV infections in neonates and infants.
- 4) Treatment of an acute HCMV infection in pregnant women.
- 5) Treatment of HCMV infection in immunosuppressed patients associated with cancer and cancer therapy.
- 6) Treatment of HCMV-positive cancer patients with the aim to reduce HCMV-mediated tumour progression (cf. J. Cinatl, et al., FEMS Microbiology Reviews 2004, 28, 59-77).
The present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, especially of infections with viruses, in particular the viruses mentioned above, and the infective diseases caused by these infections. Hereinbelow, a viral infection is to be understood as including both an infection with a virus and a disease caused by an infection with a virus.
The present invention also provides the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
The present invention also provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
The compounds according to the invention are preferably used for preparing medicaments suitable for the prophylaxis and/or treatment of infections with a representative of the group of the Herpes viridae, in particular a cytomegalovirus, in particular the human cytomegalovirus.
The present invention also provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an antivirally effective amount of the compounds according to the invention.
The present invention also provides medicaments comprising at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and/or prophylaxis of the disorders mentioned above. Active compounds suitable for combinations are, by way of example and preferably: antiviral active compounds, such as gancyclovir or acyclovir.
The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as implant or stent.
For these administration routes, it is possible to administer the compounds according to the invention in suitable administration forms.
Suitable for oral administration are known administration forms which deliver the compounds according to the invention rapidly and/or in modified form and which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example tablets provided with enteric coatings or coatings which dissolve slowly or are insoluble and which control the release of the compound according to the invention), tablets which disintegrate rapidly in the oral cavity and/or films/wafers, films/lyophylisates, capsules (for example Hart or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration can take place with avoidance of an adsorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
Examples suitable for other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops/solutions/sprays; tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations for the eyes or ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be converted into the stated administration forms.
This can take place in a known manner with the mixing of inert, non-toxic, pharmaceutically acceptable auxiliaries. These auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxides) and flavour- and/or odour-masking agents.
The present invention furthermore provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable auxiliaries, and their use for the purposes mentioned above.
In general, it has proved advantageous to administer on intravenous administration amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/kg, of body weight to achieve effective results, and the dosage on oral administration is about 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
It may nevertheless be necessary where appropriate to deviate from the amounts mentioned, specifically as a function of the body weight, administration route, individual response to the active compound, mode of preparation and time or interval over which administration takes place. Thus, it may be sufficient in some cases to make do with less than the aforementioned minimal amount, whereas in other cases the upper limit mentioned must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into a plurality of individual doses over the day.
The percentage data in the following tests and examples are percentages by weight unless otherwise indicated; parts or parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are in each case based on volume.
Abbreviations:
- BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
- CDCl3 deuterated chloroform
- DCI direct chemical ionization (in MS)
- DCM dichloromethane
- DIEA N,N-diisopropylethylamine
- DMSO dimethyl sulphoxide
- DMF N,N-dimethylformamide
- EA ethyl acetate
- EI electron impact ionization (in MS)
- ESI electrospray ionization (in MS)
- h hour
- HPLC high-pressure, high-performance liquid chromatography
- LC-MS liquid-chromatography-coupled mass spectroscopy
- LDA lithium diisopropylamide
- min minutes
- m.p. melting point
- MS mass spectroscopy
- MTBE methyl tert-butyl ether
- NMR nuclear magnetic resonance spectroscopy
- Pd-C palladium-on-carbon
- RP-HPLC reverse phase HPLC
- RT room temperature
- Rt retention time (in HPLC)
- THF tetrahydrofuran
- TLC Thin-layer chromatography.
General LC-MS and HPLC methods:
Method 1 (analytical HPLC): column: Kromasil C18 60 mm×2 mm; temperature: 30° C.; flow rate: 0.75 ml/min; mobile phase A: 0.005 M HClO4, mobile phase B: acetonitrile; gradient: →0.5 min 98% A, →4.5 min 10% A, →6.5 min 10% A.
Method 2 (preparative HPLC): column: GromSil C18, 250 mm×30 mm; flow rate: 50 ml/min; time per run: 38 min; detection: 210 nm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% B (3 min)->90% B (31 min)->90% B (34 min)->10% B (34.01 min).
Method 3 (LC-MS): column: GromSil 120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min; UV detection: 208-400 nm.
Method 4 (preparative HPLC, separation of enantiomers, carboxylic acids): column: packing chiral silica gel selector KBD 8361 (420 mm×100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide) poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound is dissolved in methyl tert-butyl ether/ethyl acetate (9:1).
Method 5 (preparative HPLC): column: GromSil C18, 250 mm×30 mm; flow rate: 50 ml/min; time per run: 38 min; detection: 210 nm; mobile phase A: water with 0.1% formic acid, mobile phase B: acetonitrile; gradient: 10% B (3 min)->90% B (31 min)->90% B (34 min)->10% B (34.01 min).
Method 6 (analytical HPLC): instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm×2 mm, 3.5 μm; mobile phase A: 5 ml of HClO4/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; flow rate: 0.75 ml/min; temp.: 30° C.; detection: UV 210 nm.
Method 7 (LC-MC): instrument: Micromass Platform LCZ with HPLC Agilent series 1100; column: GromSIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
Method 8 (LC-MC): instrument: Micromass Platform LCZ, HP 1100; column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: acetonitrile+0.1% formic acid, mobile phase B: water+0.1% formic acid; gradient: 0.0 min 10% A→4.0 min 90% A→6.0 min 90% A; oven: 40° C.; flow rate: 0.5 ml/min; UV detection: 208-400 nm.
Method 9 (LC-MC): MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm×4.6 mm; mobile phase A: water+500 μl of 50% strength formic acid/l, mobile phase B: acetonitrile+500 μl of 50% strength formic acid/l; gradient: 0.0 min 10% B→3.0 min 95% B→4.0 min 95% B; oven: 35° C.; flow rate: 0.0 min 1.0 ml/min→3.0 min 3.0 ml/min→4.0 min 3.0 ml/min; UV detection: 210 nm.
Method 10 (LC-MC): MS instrument: Micromass ZQ; HPLC instrument: HP 1100 Series; UV DAD; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; mobile phase A: water+500 μl of 50% strength formic acid/l, mobile phase B: acetonitrile+500 μl of 50% strength formic acid/l; gradient: 0.0 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B; oven: 50° C.; flow rate: 0.8 ml/min; WV UV detection: 210 nm.
Method 11 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 8361 (250 mm×20 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether+5% ethyl acetate; flow rate: 25 ml/min.
Method 12 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 5326 (250 mm×20 mm) based on the selector poly(N-methacryloyl-L-leucine-dicyclopropylmethylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether+5% ethyl acetate; flow rate: 25 ml/min.
Method 13 (preparative HPLC, separation of enantiomers): column: packing chiral silica gel selector KBD 8361 (250 mm×20 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 25 ml/min.
Method 14 (preparative HPLC, separation of enantiomers, esters): column: packing chiral silica gel selector KBD 8361 (420 mm×100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: isohexane/ethyl acetate 85/15 v/v; flow rate: 100 ml/min; the compound is dissolved in isohexane/ethyl acetate (85:15).
Method 15 (preparative HPLC, separation of enantiomers, esters): column: packing chiral silica gel selector KBD 8361 (420 mm×100 mm) based on the selector poly(N-methacryloyl-L-leucine-1-menthylamide poly(N-methacryloyl-L-leucine-1-methylamide); temperature: 23° C.; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound is dissolved in methyl tert-butyl ether.
Method 16 (LC-MS): instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A: 1 l of water+1 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+1 ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate: 0.8 m/min; UV detection: 208-400 nm.
Method 17 (LC-MS): MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; mobile phase A: water+500 μl of 50% strength formic acid/l, mobile phase B: acetonitrile+500 μl of 50% strength formic acid/l; gradient: 0.0 min 0% B→0.2 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B; oven: 45° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
Starting Materials
General Procedure [A]: Synthesis of Substituted 2-aminocinnamic Acid Derivatives by Heck Coupling from 2-halo-substituted Anilines
In a one-necked flask, 1.0 equivalent of an aryl halide is initially charged with 1.6 equivalents of methyl acrylate or tert-butyl acrylate, 2.0 equivalents of triethylamine, 0.03 equivalents of palladium(II) acetate and 0.03 equivalents of trio-tolylphosphine tri-o-tolylphosphine in acetonitrile (solution about 1M). The mixture is stirred under reflux for 48 hours. After the reaction has ended (the reaction is monitored by TLC), the solvent is removed. The residue is purified chromatographically on silica gel using cyclohexane/ethyl acetate=8:2 v/v.
Methyl (2E)-3-[2-amino-3-fluorophenyl]propenoate
Starting with 42.00 g (221.04 mmol) of 2-bromo-6-fluoroaniline, the general procedure [A] gives 29.66 g (68% of theory) of product.
HPLC (Method 1): Rt=4.14 min
MS (ESI-pos): m/z=196 (M+H)+
Methyl 2-amino-3-[(1E)-3-methoxy-3-oxo-1-propenyl]benzoate
Starting with 2.00 g (8.69 mmol) of methyl 2-amino-3-bromobenzoate, the general procedure [A] gives 1.29 g (60% of theory) of product.
HPLC (Method 1): Rt=4.42 min
MS (ESI-pos): m/z=236 (M+H)+
Methyl (2E)-3-(2-amino-3,5-difluorophenyl)-2-propenoate
Starting with 3.00 g (14.42 mmol) of 2-bromo-4,6-difluoroaniline, the general procedure [A] gives 1.41 g (45% of theory) of product.
HPLC (Method 1): Rt=4.23 min
MS (ESI-pos): m/z=214 (M+H)+
Methyl 4-amino-3-[(1E)-3-methoxy-3-oxo-1-propenyl]benzoate
Starting with 25.00 g (90.23 mmol) of methyl 4-amino-3-iodobenzoate, the general procedure [A] gives 24.31 g (92% of theory) of product.
HPLC (Method 1): Rt=4.71 min
MS (ESI-pos): m/z=278 (M+H)+
Methyl (2E)-3-[2-amino-5-cyanophenyl]-2-propenoate
Starting with 1.90 g (9.64 mmol) of 3-bromo-4-aminobenzonitrile, the general procedure [A] gives 1.28 g (50% of theory) of product.
HPLC (Method 1): Rt=2.85 min
MS (DCI-pos): m/z=220 (M+NH4)+
General Procedure [B]: Synthesis of substituted 2-nitrocinnamic acid derivatives by Wittig-Horner reaction from 2-halo-substituted benzaldehydes
In a 100 ml one-necked flask, 27.5 mmol of methyl diethyl phosphonoacetate, 25.0 mmol of the benzaldehyde and 27.5 mmol of lithium hydroxide are suspended in tetrahydrofuran. After the reaction has ended (the reaction is monitored by TLC), the reaction mixture is mixed with the same volume of water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is removed. The product is dried under high vacuum at RT, without further purification. If the product is very impure, it is, if appropriate, purified by column chromatography on silica gel using cyclohexane/ethyl acetate.
Methyl (2E)-3-(3-methoxy-2-nitrophenyl)-2-propenoate
Starting with 2.00 g (11.04 mmol) of 3-methoxy-2-nitrobenzaldehyde, the general procedure [B] gives 2.46 g (92% of theory) of product.
HPLC (Method 1): Rt=4.37 min
MS (ESI-pos): m/z=238 (M+H)+
Methyl (2E)-3-(5-fluoro-2-nitrophenyl)-2-propenoate
Starting with 20.0 g (118.3 mmol) of 5-fluoro-2-nitrobenzaldehyde, the general procedure [B] gives 7.25 g (27% of theory) of product.
MS (DCI): m/z=243 (M+NH4)+
General Procedure [C]: Preparation of a 2-nitrobenzaldehyde from a Benzyl Halide
10.0 mmol of the benzyl halide, 4.1 g of molecular sieve 4 Å and 20.0 mmol of N-methylmorpholine N-oxide are suspended in 45 ml of acetonitrile. The mixture is stirred at RT until the reaction has gone to completion (the reaction is monitored by TLC). After the reaction has ended, the molecular sieve is filtered off, the solvent is removed and the residue is taken up again in ethyl acetate. This solution is initially washed with 1N hydrochloric acid and then with saturated sodium chloride solution. The organic phase is separated off and then dried over sodium sulphate, and the solvent is again removed. Analysis shows that the crude product is sufficiently pure and can directly be reacted further.
2-Fluoro-6-nitrobenzaldehyde
Starting with 2.00 g (8.55 mmol) of 3-fluoro-6-nitrobenzyl bromide, the general procedure [C] gives 1.09 g (75% of theory) of product.
HPLC (Method 1): Rt=3.58 min
General Procedure [D]: Reduction of the Nitro Group of the 2-nitrocinnamic Acid Derivatives
Under argon, 25 mmol of the nitro compound and 125 mmol of tin(II) chloride dihydrate are initially charged in 60 ml of absolute ethanol in a 250 ml two-necked flask. This suspension is stirred under reflux for 30 minutes, and a clear solution is formed. The solution is then cooled to room temperature and subsequently poured onto ice-water. Using either solid sodium bicarbonate or a saturated sodium carbonate solution, the pH is adjusted to pH=7-8. 60 ml of ethyl acetate are then added, and the precipitated tin salts are filtered off through kieselguhr (a layer of a thickness of about 1 cm). The organic phase is separated off and the aqueous phase is re-extracted with ethyl acetate. The organic phases are combined, washed once with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is concentrated to about half of its original volume. Activated carbon corresponding to 1% of the weight of the nitro compound is then added, and the mixture is heated under reflux for 30 minutes (the colour of the solution changes). The activated carbon is filtered off and the solvent is removed.
The residue obtained is an oil which, on drying at RT under high vacuum, forms crystals. Without further purification, the product is directly used for the next step.
Methyl 3-[2-amino-6-fluorophenyl]propenoate
Starting with 7.25 g (32.2 mmol) of the nitro compound from Example 7A, the general procedure [D] gives 5.0 g (58% of theory) of product.
HPLC (Method 1): Rt=3.33 min
General Procedure [E]: Synthesis of the Iminophosphoranes by Appel Reaction of the Substituted Anilines
In a 50 ml one-necked flask, 10.0 mmol of the amine of the 2-aminocinnamic ester, 20.0 mmol of triphenylphosphine, 100.0 mmol of carbon tetrachloride and 100.0 mmol of triethylamine are dissolved in 20 ml of acetonitrile. The mixture is stirred at room temperature for 2 hours. After the reaction has ended (the reaction is monitored by TLC or analytic HPLC), the solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel using cyclohexane/ethyl acetate=7:3.
Methyl (2E)-3-{3-fluoro-2-[(triphenylphosphoranylidene)amino]phenyl}propenoate
Starting with 29.3 g (150.1 mmol) of the amine compound from Example 1A, the general procedure [E] gives 55.0 g (80% of theory) of product.
HPLC (Method 1): Rt=4.46 min
MS (ESI-pos): m/z=456 (M+H)+
Methyl (2E)-3-{5-fluoro-2-[(triphenylphosphoranylidene)amino]phenyl}propenoate
Starting with 50.0 g (256.2 mmol) of the amine compound from Example 9A, the general procedure [E] gives 89.6 g (77% of theory) of product.
HPLC (Method 1): Rt=4.36 min
MS (ESI-pos): m/z=456 (M+H)+
Methyl (2E)-3-{5-cyano-2-[(triphenylphosphoranylidene)amino]phenyl}propenoate
Starting with 1.24 g (4.60 mmol) of the amine compound from Example 5A, the general procedure
[E] gives 2.12 g (92% of theory) of product.
HPLC (Method 1): Rt=4.42 min
MS (ESI-pos): m/z=463 (M+H)+
General Procedure [F]: Synthesis of Phenylpiperazines by the Buchwald-Hartwig Reaction
To prepare for the reaction, the reaction flask is thoroughly dried by heating under high vacuum and vented with argon. 1.0 equivalent of the bromoaryl compound and 6.0 equivalents of piperazine in absolute toluene are initially charged in the flask (0.2-0.3M solution of the bromo compound). 0.01 equivalent of tris(dibenzylideneacetone)dipalladium and 0.03 equivalent of BINAP are then added. The reaction mixture is stirred under reflux for 16 h. The mixture is then extracted once with water, the organic phase is extracted twice with 1N hydrochloric acid and the aqueous phase is adjusted to pH 8 using 1N aqueous sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and filtered, the solvent is removed under reduced pressure and the product is dried under high vacuum overnight.
N-(4-Fluoro-3-methylphenyl)piperazine
Starting with 5.0 g (26.5 mmol) of 4-fluoro-3-methyl-1-bromobenzene, the general procedure [F] gives 4.52 g (83% of theory) of product.
HPLC (Method 1): Rt=3.54 min
MS (ESI pos): m/z=195 (M+H)+
N-(4-Fluorophenyl)-3-methylpiperazine
Starting with 1.0 g (5.71 mmol) of 4-fluoro-3-methyl-1-bromobenzene, the general procedure [F] gives 0.57 g (49% of theory) of product.
HPLC (Method 1): Rt=3.37 min
MS (DCI pos): m/z=195 (M+H)+
1-(3-Fluorophenyl)piperazine
1 g (5.71 mmol) of 3-fluorobromobenzene and 2.95 g (34.29 mmol) of piperazine are dissolved in 20 ml of toluene, and 0.77 g (8 mmol) of sodium tert-butoxide is added. In the presence of 0.11 g (0.17 mmol) of BINAP and 0.05 g (0.06 mmol) of tris(dibenzylideneacetone)dipalladium, the mixture is then stirred under reflux overnight. After cooling, ethyl acetate is added and the mixture is washed with water. The mixture is then extracted with 1N hydrochloric acid, and the aqueous phase is washed with ethyl acetate. The pH is adjusted to 8-9 and the mixture is then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvent is removed, giving the target compound.
Yield: 0.8 g (78% of theory)
HPLC (Method 1): Rt=3.4 min
MS (ESI-pos): m/z=181 (M+H)+
1-(3,4-Difluorophenyl)piperazine
In 100 ml of toluene, 5 g (25.91 mmol) of 3,4-difluorobromobenzene, 13.39 g (155.45 mmol) of piperazine, 3.49 g (36.27 mmol) of sodium tert-butoxide, 0.24 g (0.26 mmol) of tris(dibenzylidene-acetone)dipalladium and 0.48 g (0.78 mmol) of BINAP are stirred under reflux overnight. Ethyl acetate is added, the mixture is then washed with water and the organic phase is extracted with 1N hydrochloric acid. The aqueous phase is then washed with ethyl acetate and subsequently adjusted to pH 8. Using dichloromethane, the product is extracted from the aqueous phase. The extract is then dried over magnesium sulphate, the solvent is removed and the target compound is dried under reduced pressure.
Yield: 3.85 g (75% of theory)
HPLC (Method 1): Rt=3.4 min
MS (DCI): m/z=199 (M+H)+
2-Isocyanato-1-methoxy-4-(trifluoromethyl)benzene
3 g (15.69 mmol) of 2-methoxy-5-trifluoromethylaniline are dissolved in 100 ml of dichloromethane, and 6.73 g (31.39 mmol) of 1,8-bis(dimethylamino)naphthalene are added. At 0-5° C., 2.24 g (11.3 mmol) of trichloromethyl chloroformate, dissolved in 50 ml of dichloromethane, are added dropwise, and the mixture is stirred at 0° C. for 30 min and then at room temperature for 60 min. At 0° C., the mixture is washed with 1N hydrochloric acid, ice-water and sodium bicarbonate solution. Drying over magnesium sulphate and removal of the solvent by distillation gives the product. The isocyanate is then used for the subsequent reactions without further purification.
Yield: 3.00 g (88% of theory)
Methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]imino}methylene)amino]-phenyl}-2-propenoate
5.0 g (10.98 mmol) of methyl (2E)-3-{3-fluoro-2-[(triphenylphosphoranylidene)amino]phenyl}-2-propenoate (Example 10A) are initially charged in 50 ml of dichloromethane, and the mixture is stirred with 2.5 g (11.53 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene (Example 17A) at room temperature overnight. The solvent is removed by distillation and the product is then purified by chromatography on silica gel (isohexane/dichloromethane 2:1; 1:1) and recrystallized from isohexane.
Yield: 2.69 g (62% of theory)
HPLC (Method 1): Rt=5.6 min
MS (ESI-pos): m/z=395 (M+H)+
General Procedure [G]: Reaction of the Iminophosphorane with an Isocyanate and Subsequent Reaction with an Amine to Give the Dihydroquinazoline Derivative
1.0 equivalent of the iminophosphorane is dissolved in 20 ml of dichloromethane (0.1-0.2M solution). 1.05 equivalents of a substituted isocyanate are then added, and the mixture is stirred at RT until the reaction has ended. The reaction is monitored by TLC or by analytical HPLC.
1.0 equivalent of amine and a spatula tip of silica gel are then added to the resulting solution of the carbodiimide and dichloromethane, and the mixture is stirred at room temperature until the reaction has gone to completion. After the reaction has ended (reaction is monitored by TLC or HPLC), the mixture is concentrated and purified by preparative HPLC on an RP phase.
In certain cases, the NMR shows the presence of a varying proportion of non-cyclized reaction product. In those cases, the mixture of cyclized and non-cyclized product is taken up in dioxane, a spatula tip of silica gel is added and the mixture is stirred under reflux for 30 min to 16 h. The silica gel is filtered off and the solution is used for further reactions.
If it is intended to produce enantiomerically pure compounds, the chromatographic separation is carried out at this stage.
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 92.5 mg (0.2 mmol) of the iminophosphorane from Example 10A, the general procedure [G] gives 50 mg (45% of theory) of product.
HPLC (Method 1): Rt=4.81 min
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A following the separation of enantiomers of 3.84 g of Example 19A (715 mg, 14% of theory).
HPLC (Method 1): Rt=4.81 min
MS (ESI-pos): m/z=544.9 (M+H)+
Methyl {6-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 100 mg (0.28 mmol) of the iminophosphorane from Example 1A 11A, the general procedure [G] gives 58 mg (39% of theory) of product.
HPLC (Method 1): Rt=4.80 min
Methyl {6-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A following the separation of enantiomers of 832 mg of Example 21A (368 mg, 17% of theory).
HPLC (Method 1): Rt=4.77 min
MS (ESI-pos): m/z=544.9 (M+H)+
Methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 93 mg (0.2 mmol) of the iminophosphorane from Example 10A, the general procedure [G] gives 43 mg (39% of theory) of product.
HPLC (Method 1): Rt=4.80 min
MS (ESI-pos): m/z=541.0 (M+H)+
Methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A following the separation of enantiomers of 3.31 g of Example 23A (1.18 g, 22% of theory).
HPLC (Method 1): Rt=4.80 min
MS (ESI-pos): m/z=541.0 (M+H)+
Methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 93 mg (0.2 mmol) of the iminophosphorane from Example 10A, the general procedure [G] gives 51 mg (45% of theory) of product.
HPLC (Method 1): Rt=4.62 min
MS (ESI-pos): m/z=556.7 (M+H)+
Methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A following the separation of enantiomers of 5.11 g of Example 25A (0.49 g, 9% of theory).
HPLC (Method 1): Rt=4.71 min
MS (ESI-pos): m/z=556.8 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluoro-3-methylphenyl)-1-piperazinyl]-3-[6-methoxy-3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 500 mg (2.31 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene (Example 17A) and 427 mg (2.2 mmol) of the phenylpiperazine from Example 13A, 1.03 g (79% of theory) of crude product are obtained following filtration through silica gel (cyclohexane/ethyl acetate 2:1 (v/v)). This product is reacted further without further purification.
LC-MS (Method 3): Rt=2.55 min, 2.66 min
MS (ESI-pos): m/z=589.3 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluoro-3-methylphenyl)-1-piperazinyl]-3-[6-methoxy-3-methylphenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 0.60 g (1.76 mmol) of the iminophosphorane from Example 10A, 376 mg (2.31 mmol) of 2-methoxy-5-methylphenyl isocyanate and 342 mg (1.76 mmol) of the phenylpiperazine from Example 13A, 183 mg (16% of theory) of product are obtained after purification by preparative HPLC.
HPLC (Method 1): Rt=4.77 min
MS (ESI-pos): m/z=535.2 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[6-methoxy-3-chlorophenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 423 mg (2.31 mmol) of 2-methoxy-5-chlorophenyl isocyanate and 396 mg (2.2 mmol) of 4-fluorophenylpiperazine, 621 mg (52% of theory) of product are obtained after purification by preparative HPLC.
HPLC (Method 1): Rt=4.75 min
MS (ESI-pos): m/z=541.2 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
550 mg (1.39 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A) and 251 mg (1.39 mmol) of 1-(4-fluorophenyl)piperazine are stirred in the presence of a spatula tip of silica gel in 15 ml of dichloromethane for 1 hour. After 90 hours of stirring under reflux, the product is purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Yield: 769 mg (96% of theory)
HPLC (Method 1): Rt=4.8 min
MS (ESI-pos): m/z=575 (M+H)+
Methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydro-4-quinazolinyl}acetate
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 341 mg (1.78 mmol) of 1-(3-methoxyphenyl)piperazine and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for one hour and then under reflux for 35 hours. The target compound is obtained after purification on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Yield: 1012 mg (97% of theory)
HPLC (Method 6): Rt=4.8 min
MS (ESI-pos): m/z=587 (M+H)+
Methyl {8-fluoro-2-[4-(3,4-difluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydro-4-quinazolinyl}acetate
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 352 mg (1.78 mmol) of 1-(3,4-difluorophenyl)piperazine (Example 16A) and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is then purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Yield: 1027 mg (97% of theory)
HPLC (Method 1): Rt=4.8 min
MS (ESI-pos): m/z=593 (M+H)+
Methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
11.5 g (29.16 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 5.14 g (29.16 mmol) of 1-(3-methylphenyl)piperazine and a spatula tip of silica gel are stirred in 300 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The product is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1, 5:1).
Yield: 15.8 g (95% of theory)
HPLC (Method 1): Rt=4.8 min
MS (ESI-pos): m/z=571 (M+H)+
Methyl {8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
100 mg (0.25 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 45.7 mg (0.25 mmol) of 1-(3-fluorophenyl)piperazine (Example 15A) and a spatula tip of silica gel are stirred in 15 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Yield: 139.2 mg (96% of theory)
HPLC (Method 1): Rt=4.8 min
MS (ESI-pos): m/z=575 (M)+ (M+H)+
Methyl {8-fluoro-2-[4-(3-chlorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 93 mg (0.2 mmol) of the iminophosphorane from Example 10A, the general procedure [G] gives 51 mg (45% of theory) of product.
LC-MS (Method 3): Rt=4.78 min
MS (ESI-pos): m/z=561 (M+H)+
Methyl {8-fluoro-2-[4-(1,3-benzodioxol-5-yl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 4.19 g (9.2 mmol) of the iminophosphorane from Example 10A, the general procedure [G] gives 3.67 g (70% of theory) of product.
HPLC (Method 1): Rt=4.67 min
MS (ESI-pos): m/z=571 (M+H)+
Methyl 4-amino-3-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]benzoate
Starting with 25.0 g (90.2 mmol) of methyl 4-amino-3-iodobenzoate, the general procedure [A] gives 24.3 g (88% of theory) of product.
HPLC (Method 1): Rt=4.71 min
MS (DCI-pos): m/z=295 (M+NH4)+
Methyl (2E)-3-(4-cyano-2-nitrophenyl)-2-propenoate
Starting with 3.00 g (17.0 mmol) of 4-cyano-2-nitrobenzaldehyde, the general procedure [B] and recrystallization from methanol gives 2.51 g (63% of theory) of product.
HPLC (Method 1): Rt=4.06 min
MS (ESI-pos): m/z=233 (M+H)+
Methyl 3-[2-amino-7-cyanophenyl]propenoate
Starting with 1.0 g (4.31 mmol) of the nitro compound from Example 38A, the general procedure [D] (but without boiling over activated carbon) gives 793 mg (89% of theory) of product.
HPLC (Method 1): Rt=3.99 min
Methyl (2E)-3-{6-cyano-2-[(triphenylphosphoranylidene)amino]phenyl}propenoate
Starting with 0.75 g (3.71 mmol) of the amine compound from Example 39A, the general procedure [E] gives 1.09 g (62% of theory) of product.
HPLC (Method 1): Rt=4.30 min
MS (ESI-pos): m/z=463 (M+H)+
Methyl 3-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-4-[(triphenylphosphoranylidene)amino]-benzoate
Starting with 19.0 g (68.5 mmol) of the amine compound from Example 37A, the general procedure [E] gives 31.4 g (85% of theory) of product.
HPLC (Method 1): Rt=4.69 min
MS (ESI-pos): m/z=538 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A by separating the racemate from Example 30A chromatographically according to Method 15 in to into the enantiomers. Starting with 231 g of racemate, 120 g of the target product, which is directly reacted further, are obtained.
MS (ESI-pos): m/z=575 (M+H)+
Methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydro-4-quinazolinyl}acetate
The compound is obtained as enantiomer A by separating the racemate from Example 31A chromatographically according to Method 15 into the enantiomers. Starting with 231 g of racemate, 111 g (48% of theory) of the target product are obtained.
MS (ESI-pos): m/z=587 (M+H)+
Methyl {6-cyano-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 400 mg (0.6 mmol) of the iminophosphorane from Example 12A, the general procedure [G] gives 166 mg (48% of theory) of product.
HPLC (Method 1): Rt=4.65 min
MS (ESI-pos): m/z=552 (M+H)+
Methyl {7-cyano-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
Starting with 1.0 g (2.16 mmol) of the iminophosphorane from Example 40A, the general procedure [G] gives 1.07 g (98% of theory) of product.
HPLC (Method 1): Rt=4.72 min
MS (ESI-pos): m/z=552 (M+H)+
Methyl 4-(2-tert-butoxy-2-oxoethyl)-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)-phenyl]-3,4-dihydroquinazoline-6-carboxylate
Starting with 4.2 g (9.3 mmol) of the iminophosphorane from Example 41A, the general procedure [G] gives 3.9 g (51% of theory) of product.
HPLC (Method 1): Rt=5.03 min
MS (ESI-pos): m/z=627 (M+H)+
Methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate
This compound is obtained as enantiomer A following the separation of enantiomers of 3.5 g of Example 46A (1.4 mg, 20% of theory).
HPLC (Method 1): Rt=4.91 min
MS (ESI-pos): m/z=627 (M+H)+
4-(2-tert-Butoxy-2-oxoethyl)-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-6-carboxylic acid
1.3 g (2.0 mmol) of the methyl carboxylate from Example 47A are dissolved in 12 ml of dioxane, 2.4 ml of an aqueous 1N solution of potassium hydroxide are added and the mixture is stirred at 60° C. for 5 hours. The pH is adjusted to pH=4 using an aqueous 1N solution of hydrochloric acid and the reaction mixture is concentrated and purified by preparative HPLC. This gives 580 mg (48% of theory) of the product.
HPLC (Method 1): Rt=4.85 min
MS (ESI-pos): m/z=613 (M+H)+
Tert-butyl {6-(aminocarbonyl)-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate
560 mg (0.9 mmol) of the carboxylic acid from Example 48A, 2.6 mmol of aluminium chloride, 1.1 mmol of 1-hydroxy-1H-benzotriazole hydrate and 1.1 mmol of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide are suspended in DMF. 2.6 mmol of N,N-diisopropylamine are added, and the mixture is stirred at room temperature for 16 hours. 20 ml of ethyl acetate are added to the reaction mixture, which is then washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The combined aqueous phases are adjusted to pH=8 and extracted with ethyl acetate. The combined organic phases are finally washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. This gives 548 mg (97% of theory) of product.
HPLC (Method 1): Rt=4.73 min
MS (ESI-pos): m/z=612 (M+H)+
Examples 50A to 112A 111A of Table 1 can be prepared from the corresponding starting materials using the general procedures [A] to [G].
TABLE 1 | ||||
Example | R | HPLC | MS ESIpos. | |
No. | Structure | [min] | method | [M + H]+ |
50A |
|
4.53 | 1 | 561 [M + H − HCl]+ |
51A |
|
4.22 | 1 | 556 [M + H − HCl]+ |
52A |
|
4.36 | 1 | 552 [M + H − HCl]+ |
53A |
|
4.37 | 1 | 572 [M + H − HCl]+ |
54A |
|
4.54 | 1 | 549 [M + H − HCl]+ |
55A |
|
4.27 | 1 | 568 [M + H − HCl]+ |
56A |
|
4.30 | 1 | 538 |
57A |
|
4.28 | 1 | 518 |
58A |
|
4.41 | 1 | 538 |
59A |
|
4.82 | 1 | 557 |
60A |
|
4.61 | 1 | 549 [M + H − HCl]+ |
61A |
|
4.89 | 1 | 517 |
62A |
|
4.81 | 6 | 605 |
63A |
|
4.60 | 6 | 591 |
64A |
|
4.85 | 6 | 591 |
65A |
|
4.92 | 6 | 609 |
66A |
|
4.83 | 1 | 603 |
67A |
|
4.78 | 1 | 587 |
68A |
|
5.13 | 1 | 563 |
69A |
|
4.76 | 1 | 563 |
70A |
|
4.81 | 1 | 581 |
71A |
|
5.21 | 1 | 581 |
72A |
|
5.21 | 1 | 575 |
73A |
|
4.98 | 1 | 559 |
74A |
|
4.86 | 1 | 591 |
75A |
|
4.86 | 6 | 593 |
76A |
|
4.94 | 1 | 547 |
77A |
|
4.82 | 1 | 539 |
78A |
|
4.92 | 1 | 589 |
79A |
|
4.57 | 1 | 582 |
80A |
|
2.38 | 3 | 495 |
81A |
|
1.95 | 9 | 491 |
82A |
|
1.97 | 9 | 507 |
83A |
|
1.93 | 9 | 511 |
84A |
|
1.90 | 9 | 487 |
85A |
|
4.87 | 1 | 541 |
86A |
|
4.91 | 1 | 561 |
87A |
|
4.76 | 1 | 557 |
88A |
|
4.65 | 1 | 552 |
89A |
|
4.77 | 1 | 568 |
90A |
|
4.62 | 1 | 564 |
91A |
|
5.00 | 1 | 609 |
92A |
|
4.70 | 1 | 563 |
93A |
|
577 | ||
94A |
|
4.74 | 1 | 545 |
95A |
|
4.90 | 1 | 605 |
96A |
|
4.83 | 1 | 563 |
97A |
|
4.82 | 1 | 537 |
98A |
|
4.90 | 1 | 557 |
99A |
|
4.81 | 1 | 553 |
100A |
|
|||
101A |
|
4.78 | 1 | 521 |
102A |
|
4.73 | 1 | 517 |
103A |
|
3.10 | 16 | 533 |
104A |
|
2.75 | 17 | 555 |
105A |
|
2.95 | 17 | 555 |
106A |
|
4.74 | 1 | 545 |
107A |
|
4.93 | 1 | 541 |
108A |
|
5.08 | 1 | 575 |
109A |
|
4.88 | 1 | 563 |
110A |
|
4.54 | 1 | 531 [M + H − HCl]+ |
111A |
|
4.54 | 1 | 571 [M + H − HCl]+ |
General Procedure [H]: Hydrolysis of the Quinazolylacetic Acid Esters
1.0 equivalent of the quinazolyl ester are dissolved in dioxane, and 5.0 equivalents of 1N aqueous sodium hydroxide solution are added. The mixture is stirred at 80° C. for 16 hours, and after the reaction has ended (the reaction is monitored by analytical HPLC) the mixture is concentrated. The residue is then taken up in water and adjusted to pH 5 using 1N hydrochloric acid. The resulting precipitate is filtered off, washed with a little water and diethyl ether and dried at room temperature under high vacuum. Alternatively, the precipitate can be filtered off through an Extrelute cartridge, then washed with ethyl acetate, followed by concentration of the filtrate. If the purity of the product is not high enough, the product is purified either by preparative HPLC on an RP phase (Method 2 or Method 5) or on silica gel using mixtures of cyclohexane/ethyl acetate.
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 37 mg (0.07 mmol) of the methyl ester from Example 19A, the general procedure [H] gives 29 mg (80% of theory) of product.
HPLC (Method 1): Rt=4.49 min
MS (ESI-pos): m/z=530.7 (M+H)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.59 (s, 1H); 7.45 (t, 1H); 7.37 (t, 2H); 7.02-6.95 (m, 3H); 6.93-6.85 (m, 4H); 5.24 (dd, 1H); 2.98 (db, 4H); 2.91 (db, 4H); 2.73 (dd, 1H); 2.54 (dd, 1H).
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 695 mg (1.27 mmol) of the methyl ester from Example 20A, the general procedure [H] gives 488 mg (64% of theory) of product.
HPLC (Method 1): Rt=4.59 min
MS (ESI-pos): m/z=530.8 (M+H)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.60 (s, 1H); 7.47-7.40 (m, 3H); 7.03-6.86 (m, 7H); 5.26-5.23 (m, 1H); 3.60-3.52 (m, 4H); 2.99-2.90 (m, 4H); 2.75 (dd, 1H); 2.56 (dd, 1H).
{8-Fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 34 mg (0.06 mmol) of the methyl ester from Example 23A, the general procedure [H] gives 30 mg (90% of theory) of product.
HPLC (Method 1): Rt=4.56 min
MS (ESI-pos): m/z=526.9 (M+H)+
1H NMR (200 MHz, DMSO-d6): δ [ppm]=7.64 (s, 1H); 7.53 (t, 1H); 7.44-7.34 (m, 2H); 7.11-6.90 (m, 3H); 6.72-6.59 (m, 4H); 5.33-5.25 (m, 1H); 3.52 (db, 4H); 3.02 (db, 4H); 2.69-2.55 (m, 2H, partially obscured by DMSO signal); 2.23 (s, 3H).
{8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 36 mg (0.07 mmol) of the methyl ester from Example 25A, the general procedure [H] and chromatography (Method 2) give 28 mg (77% of theory) of product.
HPLC (Method 1): Rt=4.46 min
MS (ESI-pos): m/z=542.9 (M+H)+
1H NMR (200 MHz, DMSO-d6): δ [ppm]=7.67 (s, 1H); 7.54 (t, 1H); 7.45-7.38 (m, 2H); 7.14-6.94 (m, 3H); 6.51-6.35 (m, 4H); 5.35-5.25 (m, 1H); 3.69 (s, 3H); 3.50 (db, 4H); 3.06 (db, 4H); 2.58-2.52 (m, 2H).
{8-Fluoro-2-[4-(3-chlorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 38 mg (0.07 mmol) of the methyl ester from Example 35A, the general procedure [H] gives 25 mg (66% of theory) of product.
HPLC (Method 1): Rt=4.64 min
MS (ESI-pos): m/z=546.9 (M+H)+
1H NMR (200 MHz, DMSO dd6): δ [ppm]=7.66 (s, 1H); 7.52 (t, 1H); 7.38 (dd, 2H); 7.20 (t, 1H); 7.10-6.78 (m, 6H); 5.33-5.26 (m, 1H); 3.51 (db, 4H); 3.11 (db, 4H); 2.61-2.55 (m, 2H).
{8-Fluoro-2-[4-(1,3-benzodioxol-5-yl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 173 mg (0.30 mmol) of the methyl ester from Example 36A, the general procedure [H] gives 79 mg (46% of theory) of product.
HPLC (Method 1): Rt=4.44 min
MS (ESI-pos): m/z=557.2 (M+H)+
1H NMR (300 MHz, CDCl3): δ [ppm]=7.47 (s, 1H); 7.42-7.34 (m, 3H); 7.03-6.89 (m, 2H); 6.79 (d, 1H); 6.64 (d, 1H); 6.41 (d, 1H); 6.22 (dd, 1H); 5.87 (s, 2H); 5.20-5.15 (m, 1H); 3.59 (sb, 3H); 2.94-2.85 (m, 5H); 2.59 (dd, 1H).
{6-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Starting with 42 mg (0.08 mmol) of the methyl ester from Example 21A, the general procedure [H] gives 34 mg (76% of theory) of product.
HPLC (Method 1): Rt=4.63 min
MS (ESI-pos): m/z=530.9 (M+H)+
{6-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 350 mg (0.64 mmol) of the ester from Example 22A, the general procedure [H] gives 284 mg (83% of theory) of product.
HPLC (Method 1): Rt=4.53 min
MS (ESI-pos): m/z=530.8 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.62 (s, 1H); 7.51-7.48 (m, 1H); 7.43-7.41 (d, 1H); 7.26-7.23 (m, 1H); 7.04-6.95 (m, 2H); 6.91-6.85 (m, 3H); 5.23 (dd, 1H); 3.55 (sb, 3H); 3.02-2.99 (m, 1H); 2.94 (sb, 4H); 2.80 (dd, 1H).
{8-Fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 1.10 g (1.93 mmol) of the ester from Example 24A, the general procedure [H] gives 1.04 g (91% of theory) of product. Following the separation of enantiomers by Method 4, the product is obtained as enantiomer A.
HPLC (Method 1): Rt=4.68 min
MS (ESI-pos): m/z=526.9 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.61 (s, 1H); 7.49-7.38 (m, 3H); 7.10-6.89 (m, 4H); 6.71-6.65 (m, 3H); 5.26 (dd, 1H); 3.60-3.52 (m, 4H); 3.03-2.95 (m, 4H); 2.76 (dd, 1H); 2.57 (dd, 1H); 2.25 (s, 3H).
{8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 437 mg (0.79 mmol) of the ester from Example 26A, the general procedure [H] gives 344 mg (72% of theory) of product.
HPLC (Method 1): Rt=4.48 min
MS (ESI-pos): m/z=543.0 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.61 (s, 1H); 7.49-7.38 (m, 3H); 7.14-6.89 (m, 4H); 6.47-6.39 (m, 3H); 5.26 (dd, 1H); 3.72 (s, 1H); 3.60-3.54 (m, 4H); 3.07-3.00 (m, 4H); 2.77 (dd, 1H); 2.57 (dd, 1H).
{8-Fluoro-2-[4-(4-fluoro-3-methylphenyl)-1-piperazinyl]-3-[6-methoxy-3-(trifluoromethyl)-phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 1.03 g (1.75 mmol) of the crude product of the ester from Example 27A, the general procedure [H] and chromatography according to Method 5 followed by dissolution of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent give 283 mg (22% of theory) of hydrochloride.
HPLC (Method 1): Rt=4.58 min
MS (ESI-pos): m/z=575.2 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=8.17 (s, 0.66H); 7.69 (d, 1H); 7.55-7.30 (m, 1H); 7.27-7.24 (m, 2H); 7.16 (d, 0.6H); 7.09-7.04 (m, 2H); 5.33-5.27, 5.12-5.06 (2×m, 1H); 4.08-3.35 (m, 4H); 3.69 (s, 3H); 3.30-3.22 (m, 1H); 2.80-2.76 (m, 1H); 2.25 (s, 3H).
{8-Fluoro-2-[4-(4-fluoro-3-methylphenyl)-1-piperazinyl]-3-[6-methoxy-3-(trifluoromethyl)-phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Prior to the separation of enantiomers, 268 mg of the hydrochloride from Example 11 are taken up in dichloromethane, and the organic phase is extracted twice with saturated sodium bicarbonate solution. The combined aqueous phases are extracted once with dichloromethane, the combined organic phases are dried over sodium sulphate and filtered and the solvent is removed under reduced pressure. This gives 204 mg (86% of theory) of the free base. Using this material, separation of enantiomers (Method 4), re-purification by preparative HPLC (Method 5) and subsequent dissolution of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent gives 80 mg (78% of theory) of enantiomer A.
HPLC (Method 6): Rt=4.66 min
MS (ESI-pos): m/z=575.2 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=8.17 (s, 0.66H); 7.69 (d, 1H); 7.45-7.30 (m, 1H); 7.24 (d, 2H); 7.15 (d, 0.7H); 7.08-7.01 (m, 2H); 5.32-5.27, 5.11-5.07 (2×m, 1H); 4.06-3.50 (m, 4H); 3.68 (s, 3H); 3.33-3.24 (m, 1H); 2.77-2.72 (m, 1H); 2.24, 2.23 (2×s, 3H).
{8-Fluoro-2-[4-(4-fluoro-3-methylphenyl)-1-piperazinyl]-3-[6-methoxy-3-methylphenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 183 mg (0.34 mmol) of the crude product of the ester from Example 28A, the general procedure [H] and chromatography according to Method 5 followed by dissolution of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent give 135 mg (67% of theory) of hydrochloride.
HPLC (Method 1): Rt=4.67 min
MS (ESI-pos): m/z=521.2 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.69-7.42 (m, 4H); 7.25-7.06 (m, 5H); 6.93-6.78 (m, 1H); 5.24-5.21, 5.06-5.03 (2×m, 1H); 4.00-3.35 (m, 8H); 3.21-3.08 (m, 1H); 3.01-2.77 (m, 1H); 2.34, 2.20 (2×s, 3H); 2.26 (s, 3H).
{8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
At room temperature, 179.6 mg (4.49 mmol) of sodium hydroxide are added to 878 mg (1.5 mmol) of methyl {8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 31A) in 40 ml of dioxane, and the mixture is stirred at 50° C. for 2 hours. The pH is then adjusted to 4-5. The product is filtered off, washed with water and dried under reduced pressure.
Yield: 801 mg (93% of theory)
HPLC (Method 1): Rt=4.5 min
MS (ESI-pos): m/z=573 (M+H)+
{8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
After separation of enantiomers (Method 11) of 500 mg of racemate (Example 14), the crude product is purified by chromatography on silica gel and then dissolved in 1N aqueous sodium hydroxide solution and extracted with diethyl ether. Following acidification with 1N hydrochloric acid, the product is filtered off and dried under reduced pressure.
Yield: 105 mg (21% of theory)
MS (ESI-pos): m/z=573 (M+H)+
1H NMR (300 MHz, DMSO-d6): δ [ppm]=2.4-2.5 (m, 1H); 2.7-3.1 (m, 5H); 3.3-3.6 (m, 4H); 3.7 (s, 3H); 3.7-3.9 (sb, 3H); 4.8-5.05 (sb, 1H); 6.3-6.4 (m, 2H); 6.4-6.5 (m, 1H); 6.8-7.65 (m, 6H); 12.5 (sb, 1H).
Alternatively, the target product is obtained by reacting the enantiomerically pure ester from Example 43A according to the general procedure [H]. Starting with 111 g (0.19 mol) of ester, 69 g (63% of theory) of target product are obtained.
{8-Fluoro-2-[4-(3,4-difluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
In 40 ml of dioxane, 881 mg (1.49 mmol) of methyl {8-fluoro-2-[4-(3,4-difluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 32A) and 178 mg (4.46 mmol) of sodium hydroxide are stirred at 50° C. for 2 hours. Following acidification with 1N hydrochloric acid, the product is filtered off with suction, washed with water and dried under reduced pressure.
Yield: 775 mg (90% of theory)
HPLC (Method 1): Rt=4.5 min
MS (ESI-pos): m/z=579 (M+H)+
{8-Fluoro-2-[4-(3,4-difluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Following the separation of enantiomers (Method 12) of 500 mg (0.86 mmol) of racemate (Example 16), the crude product is purified by chromatography on silica gel (dichloromethane, dichloromethane/methanol 20:1, 10:1), dissolved in 1N aqueous sodium hydroxide solution and extracted with diethyl ether. Using 1N hydrochloric acid the aqueous phase is adjusted to pH 4-5, and the product is filtered off, washed with water and dried under reduced pressure.
Yield: 86 mg (17% of theory)
MS (ESI-pos): m/z=579 (M+H)+
1H NMR (300 MHz, DMSO-d6): δ [ppm]=2.6-3.1 (m, 6H); 3.25-3.6 (m, 4H); 3.75 (sb, 3H); 4.85 (sb, 1H); 6.6-6.7 (m, 1H); 6.7-7.7 (m, 9H); 12.5 (sb, 1H).
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
In 800 ml of dioxane, 15 g (26.11 mmol) of methyl {8-fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 30A) and 3.13 g (78.32 mmol) of sodium hydroxide are stirred at 50° C. for 4 hours. Following distillative removal of the solvent, the residue is dissolved in 500 ml of water and acidified and the precipitate is filtered off with suction. The product is washed with water and dried under reduced pressure.
Yield: 14.5 g (99% of theory)
HPLC (Method 1): Rt=4.5 min
MS (ESI-pos): m/z=561 (M+H)+
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
14.2 g (25.33 mmol) of racemate (Example 18) are separated (Method 13). The crude product is dissolved in 250 ml of 0.5N sodium hydroxide solution and then purified by extraction with diethyl ether. After acidification of the aqueous phase with hydrochloric acid, the product is filtered off, washed with water and dried under reduced pressure.
Yield: 5.85 g (41% of theory)
MS (ESI-pos): m/z=561 (M+H)+
HPLC (Method 1): Rt=4.5 min
1H NMR (400 MHz, DMSO-D6): δ [ppm]=2.6-3.0 (m, 6H); 3.3-3.6 (m, 4H); 3.6-4.0 (sb, 3H); 4.8-5.2 (sb, 1H); 6.7-7.75 (m, 10H); 12.2-12.8 (sb, 1H).
Alternatively, the target product is obtained by reacting the enantiomerically pure ester from Example 42A according to the general procedure [11] [H]. Starting with 120 g (0.21 mol) of ester, 96 g (81% of theory) of target product are obtained.
{8-Fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
In 40 ml of dioxane, 892 mg (1.56 mmol) of methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 33A) and 187.6 mg (4.69 mmol) of sodium hydroxide are stirred at 50° C. for 2 hours. Following removal of the solvent, the residue is taken up in water and adjusted to pH 4-5 using 1N hydrochloric acid. The product is filtered off and then washed with water and dried under reduced pressure.
Yield: 788 mg (91% of theory)
MS (ESI-pos): m/z=557 (M+H)+
HPLC (Method 6): Rt=4.5 min
{8-Fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
The separation of enantiomers (Method 13) is carried out using 500 mg (0.9 mmol) of racemate (Example 20). The crude product is then dissolved in 1N aqueous sodium hydroxide solution, the solution is extracted with diethyl ether and the aqueous phase is adjusted to pH 4-5 using 1N hydrochloric acid. The product is filtered off with suction, washed with water and dried under reduced pressure.
Yield: 104 mg (21% of theory)
MS (ESI-pos): m/z=557 (M+H)+
1H NMR (400 MHz, DMSO d6)(400 MHz, DMSO-d6): δ [ppm]=2.2 (sb, 3H); 2.35-2.5 (m, 1H); 2.6-3.1 (m, 5H); 3.3-3.6 (m, 4H); 3.8 (sb, 3H); 4.9 (sb, 1H); 6.5-6.7 (m, 3H); 6.8-7.7 (m, 7H); 12.6 (sb, 1H).
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[6-methoxy-3-chlorophenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 621 mg (1.15 mmol) of the ester from Example 29A, the general procedure [H] and purification by preparative HPLC (Method 5) and coevaporation with methanol/N methanol/1N hydrochloric acid give 330 mg (51% of theory) of product.
HPLC (Method 1): Rt=4.58 min
MS (ESI-pos): m/z=527.0 (M+H−HCl)+
{8-Fluoro-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[6-methoxy-3-chlorophenyl]-3,4-dihydro-4-quinazolinyl}acetic acid hydrochloride
Starting with 320 mg (0.06 mmol) of the racemate from Example 22, chromatographic separation of enantiomers (Method 4) and subsequent dissolution of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent give 174 mg (50% of theory) of hydrochloride.
HPLC (Method 1): Rt=4.51 min
MS (ESI-pos): m/z=527.1 (M+H−HCl)+
1H NMR (400 MHz, CD3CN): δ [ppm]=7.29 (dd, 1H); 7.19-7.11 (m, 2H); 7.01-6.94 (m, 4H); 6.87-6.83 (m, 2H); 5.08 (t, 1H); 3.67 (s, 3H); 3.56 (s, 4H); 3.03-2.92 (m, 5H); 2.72 (dd, 1H).
{8-Fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
In 15 ml of dioxane, 117 mg (0.2 mmol) of methyl {8-fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 34A) are mixed with 0.61 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at 50° C. for 3 hours. After removal of the solvent, the residue is taken up in water and the mixture is adjusted to pH 34 3-4 using 1N hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried under reduced pressure.
Yield: 76 mg (67% of theory)
HPLC (Method 1): Rt=4.6 min
MS (ESI-pos): m/z=561 (M+H)+
{8-Fluoro-2-[4-(3-fluorophenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
52 mg (0.09 mmol) of the racemate (Example 24) are separated into the enantiomers (Method 13). The crude product is then purified by chromatography on silica gel (acetic acid, dichloromethane/methanol 10:1) and dried under reduced pressure.
Yield: 12.3 mg (24% of theory)
LC-MS (Method 7): Rt=2.50 min
MS (ESI-pos): m/z=561 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ [ppm]=2.35-2.5 (m, 1H); 2.7-3.1 (m, 5H); 3.3-3.6 (m, 4H); 3.8 (sb, 3H); 4.8-4.9 (m, 1H); 6.45-6.6 (m, 1H); 6.6-6.7 (m, 2H); 6.8-6.9 (m, 2H); 6.98-7.1 (m, 1H); 7.1-7.6 (m, 4H); 12.4 (sb, 1H).
Examples 26 to 34 and 36 to 89 of Table 2 can be prepared from the corresponding starting materials using the general procedures [A] to [H], and Example 35 can be prepared as described below in Table 2.
TABLE 2 | ||||||
Molecular | Starting | |||||
Example | weight | material | R4 | HPLC | ||
No. | Structure | [g/mol] | Example | [min] | Method | MS |
26 |
|
597.0 | 50A | 4.53 | 1 | 561 [M + H − HCl]+ |
27 |
|
592.0 | 51A | 4.22 | 1 | 556 [M + H − HCl]+ |
28 |
|
588.0 | 52A | 4.36 | 1 | 552 [M + H − HCl]+ |
29 |
|
608.4 | 53A | 4.37 | 1 | 572 [M + H − HCl]+ |
30 |
|
584.9 | 54A | 4.54 | 1 | 548 [M + H − HCl]+ |
31 |
|
604.0 | 55A | 4.27 | 1 | 568 [M + H − HCl]+ |
32 |
|
537.5 | 56A | 4.30 | 1 | 538 [M + H − HCl]+ |
33 |
|
517.5 | 57A | 4.28 | 1 | 518 [M + H − HCl]+ |
34 |
|
537.5 | 58A | 4.41 | 1 | 538 [M + H − HCl]+ |
35 |
|
565.0 | 89 | 4.47 | 1 | 529 [M + H]+ |
36 |
|
584.9 | 60A | 4.61 | 1 | 549 [M + H]+ |
37 |
|
502.6 | 61A | 4.6 | 1 | 503 [M + H]+ |
38 |
|
590.6 | 62A | 4.6 | 6 | 591 [M + H]+ |
39 |
|
590.6 | 63A | 4.53 | 1 | 591 [M + H]+ |
40 |
|
576.6 | 64A | 4.5 | 6 | 577 [M + H]+ |
41 |
|
594.6 | 65A | 4.5 | 6 | 595 [M + H]+ |
42 |
|
588.6 | 66A | 4.4 | 6 | 589 [M + H]+ |
43 |
|
572.6 | 67A | 4.5 | 6 | 573 [M + H]+ |
44 |
|
548.6 | 68A | 4.9 | 1 | 549 [M + H]+ |
45 |
|
548.5 | 69A | 4.67 | 1 | 549 [M + H]+ |
46 |
|
566.5 | 70A | 4.60 | 1 | 567 [M + H]+ |
47 |
|
566.6 | 71A | 4.9 | 1 | 567 [M + H]+ |
48 |
|
560.7 | 72A | 4.8 | 1 | 561 [M + H]+ |
49 |
|
544.7 | 73A | 5.0 | 1 | 545 [M + H]+ |
50 |
|
576.6 | 74A | 4.6 | 1 | 577 [M + H]+ |
51 |
|
578.5 | 75A | 4.7 | 1 | 579 [M + H]+ |
52 |
|
532.6 | 76A | 4.6 | 1 | 561 [M + H]+ |
53 |
|
524.5 | 77A | 4.5 | 1 | 525 [M + H]+ |
54 |
|
574.6 | 78A | 4.7 | 1 | 561 [M + H]+ |
55 |
|
567.6 | 79A | 4.3 | 1 | 568 [M + H]+ |
56 |
|
494.5 | 80A | 2.77 | 10 | 495 [M + H]+ |
57 |
|
490.6 | 81A | 1.94 | 9 | 491 [M + H]+ |
58 |
|
507.0 | 82A | 1.97 | 9 | 507 [M + H]+ |
59 |
|
511.0 | 83A | 1.93 | 9 | 511 [M + H]+ |
60 |
|
486.6 | 84A | 1.90 | 9 | 487 [M + H]+ |
61 |
|
526.5 | 85A | 4.69 | 1 | 527 [M + H]+ |
62 |
|
545.0 | 86A | 3.57 | 8 | 547 [M + H]+ |
63 |
|
542.5 | 87A | 3.37 | 8 | 543 [M + H]+ |
64 |
|
574.0 | 88A | 4.43 | 1 | 538 [M + H − HCl]+ |
65 |
|
590.4 | 89A | 4.58 | 1 | 554 [M + H − HCl]+ |
66 |
|
586.0 | 90A | 4.41 | 1 | 550 [M + H − HCl]+ |
67 |
|
594.5 | 91A | 4.82 | 1 | 595 [M + H]+ |
68 |
|
548.5 | 92A | 4.06 | 1 | 549 [M + H]+ |
69 |
|
562.5 | 93A | 4.74 | 1 | 563 [M + H]+ |
70 |
|
530.5 | 94A | 4.62 | 1 | 531 [M + H]+ |
71 |
|
591.5 | 95A | 4.76 | 1 | 591 [M + H]+ |
72 |
|
548.5 | 96A | 4.63 | 1 | 549 [M + H]+ |
73 |
|
523.0 | 97A | 4.65 | 1 | 523 [M + H]+ |
74 |
|
543.4 | 98A | 4.67 | 6 | 543 [M + H]+ |
75 |
|
539.0 | 99A | 4.56 | 6 | 539 [M + H]+ |
76 |
|
599.5 | 100A | 4.63 | 6 | 523 [M + H − HCl]+ |
77 |
|
506.6 | 101A | 4.52 | 6 | 507 [M + H]+ |
78 |
|
539.0 | 102A | 4.63 | 6 | 503 [M + H − HCl]+ |
79 |
|
555.0 | 103A | 4.41 | 6 | 519 [M + H − HCl]+ |
80 |
|
577.5 | 104A | 4.53 | 6 | 541 [M + H − HCl]+ |
81 |
|
541.0 | 105A | 4.68 | 1 | 541 [M + H]+ |
82 |
|
537.5 | 45A | 4.52 | 1 | 538 [M + H]+ |
83 |
|
530.5 | 106A | 4.51 | 1 | 531 [M + H]+ |
84 |
|
526.5 | 107A | 4.70 | 1 | 527 [M + H]+ |
85 |
|
583.4 | 108A | 4.61 | 1 | 547 [M + H − HCl]+ |
86 |
|
585.0 | 109A | 4.82 | 1 | 549 [M + H − HCl]+ |
87 |
|
530.5 | 110A | 4.54 | 1 | 531 [M + H]+ |
88 |
|
570.6 | 111A | 4.54 | 1 | 571 [M + H]+ |
89 |
|
579.0 | 59A | 4.60 | 1 | 543 [M + H − HCl]+ |
{2-[4-(4-Fluorophenyl)piperazin-1-yl]-8-hydroxy-3-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid
80 mg (0.14 mmol) of the methyl ether (Example 89) are dissolved in 2 ml of dichloromethane, and 0.41 mmol of a 1M solution of boron tribromide in dichloromethane is added at 0° C. The mixture is stirred at room temperature for 16 hours, a further 0.82 mmol of the boron tribromide solution is added, followed by a further 1.23 mmol after 24 hours. The reaction mixture is stirred at room temperature for 24 hours and then poured onto ice, and 5 ml of a 1N aqueous hydrochloric acid solution are added. The mixture is extracted with 25 ml of ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, concentrated and purified by preparative HPLC. This gives 50 mg (63% of theory) of product.
HPLC (Method 1): Rt=4.47 min
MS (ESI-pos): m/z=529 (M+H−HCl)+
{7-Hydroxycarbonyl-2-[4-(4-fluorophenyl)-1-piperazinyl]-3-[5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
100 mg (0.16 mmol) of the ester from Example 45A are suspended in semiconcentrated hydrochloric acid, and the reaction mixture is stirred at 90° C. for 42 hours. After cooling, the mixture is adjusted to pH=4 using 20% strength aqueous sodium hydroxide solution and the precipitate that is formed is filtered off, washed with water and dried under reduced pressure.
Yield: 64 mg (66% of theory)
HPLC (Method 1): Rt=4.38 min
MS (ESI-pos): m/z=557 (M+H)+
{6-(Aminocarbonyl)-2-[4-(4-fluorophenyl)piperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid hydrochloride
500 mg (0.8 mmol) of the tert-butyl ester from Example 49A are suspended with 8 ml of a 4M solution of hydrogen chloride in dioxane, and the reaction mixture is stirred at room temperature for 16 hours. The suspension is concentrated and dried under reduced pressure.
Yield: 564 mg (99% of theory)
HPLC (Method 1): Rt=4.25 min
MS (ESI-pos): m/z=556 (M+H−HCl)+
1H NMR (300 MHz, DMSO-D6): δ [ppm]=12.94 (brs, 1H); 8.11 (s, 1H); 8.03-7.95 (m, 2H); 7.92-7.65 (m, 4H); 7.09-6.91 (m, 4H); 5.50 (dd, 1H); 4.38-4.12 (m, 4H); 3.17-3.06 (m, 5H); 2.81 (dd, 1H).
B. Assessment of the Physiological Activity
The in vitro effect of the compounds of the invention can be shown in the following assays:
Anti-HCMV (Anti-Human Cytomegalovirus) Cytopathogenicity Tests
The test compounds are employed as 50 millimolar (mM) solutions in dimethyl sulphoxide (DMSO). Ganciclovir®, Foscarnet® and Cidofovir® are used as reference compounds. After addition of in each case 2 μl of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 μl portions of cell culture medium in row 2 A-H for duplicate determinations, 1:2 dilutions are carried out with 50 μl portions of medium up to row 11 of the 96-well plate. The wells in rows 1 and 12 each contain 50 μl of medium. In 150 μl of a suspension of 1×104 cells (human prepuce fibroblasts [NHDF]) are pipetted into each of the wells (row 1=cell control) and, in rows 2-12, a mixture of HCMV-infected and uninfected NHDF cells (M.O.I.=0.001-0.002), i.e. 1-2 infected cells per 1000 uninfected cells. Row 12 (without substance) serves as virus control. The final test concentrations are 250-0.0005 μM. The plates are incubated at 37° C./5% CO2 for 6 days, i.e. until all the cells are infected in the virus controls (100% cytopathogenic effect [CPE]). The wells are then fixed and stained by adding a mixture of formalin and Giemsa's dye (30 minutes), washed with double-distilled water and dried in a drying oven at 50° C. The plates are then assessed visually using an overhead microscope (Plaque Multiplier from Technomara).
The following data can be acquired from the test plates:
CC50 (NHDF)=substance concentration in μM at which no visible cytostatic effects on the cells are evident by comparison with the untreated cell control;
EC50 (HCMV)=substance concentration in μM which inhibits the CPE (cytopathic effect) by 50% compared with the untreated virus control;
SI (selectivity index)=CC50 (NHDF)/EC50 (HCMV).
Representative in vitro data for the effects of the compounds of the invention are shown in Table A:
TABLE A | ||||
NHDF | ||||
Example | CC50 | HCMV | SI | |
No. | [μM] | EC50 [μM] | HCMV | |
2 | 12 | 0.016 | 750 | |
9 | 15 | 0.02 | 750 | |
15 | 31 | 0.002 | 15500 | |
19 | 17 | 0.002 | 8947 | |
23 | 24 | 0.002 | 12632 | |
29 | 47 | 0.07 | 671 | |
The suitability of the compounds of the invention for the treatment of HCMV infections can be shown in the following animal model:
HCMV Xenograft Gelfoam® Model
Animals:
3-4-week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID beige, are purchased from commercial breeders (Taconic M+B, Jackson USA). The animals are housed under sterile conditions (including bedding and feed) in isolators.
Virus growing:
Human cytomegalovirus (HCMV), Davis or AD169 strain, is grown in vitro on human embryonic prepuce fibroblasts (NHDF cells). After the NHDF cells have been infected with a multiplicity of infection (M.O.I.) of 0.01-0.03, the virus-infected cells are harvested 5-10 days later and stored in the presence of minimal essential medium (MEM), 10% fetal calf serum (FCS) with 10% DMSO at 40° C. −40° C. After serial ten-fold dilutions of the virus-infected cells, the titer is determined on 24-well plates of confluent NHDF cells after vital staining with Neutral Red.
Preparation of the Sponges, Transplantation, Treatment and Evaluation:
Collagen sponges 1×1×1 cm in size (Gelfoam®; from Peasel & Lorey, order No. 407534; K. T. Chong et al., Abstracts of 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) are initially wetted with phosphate-buffered saline (PBS), the trapped air bubbles are removed by degassing, and then stored in MEM+10% FCS. 1×106 virus-infected NHDF cells (infection with HCMV Davis or HCMV AD169 M.O.I. =0.01) are detached 3 hours after infection and added in a drop of 20 μl of MEM, 10% of FCS, to a moist sponge. About 16 hours later, the infected sponges are incubated with 25 μl of PBS/0.1% BSA/1 mM DTT with 5 ng/μl basic fibroblast growth factor (bFGF). For the transplantation, the immunodeficient mice are anaesthetized with Avertin or a ketamine/xylazine/azepromazine mixture, the fur on the back is removed using a shaver, the epidermis is opened 1-2 cm, unstressed and the moist sponges are transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 6 hours after the transplantation, the mice can be treated for the first time (on the day of the operation, there is one treatment). The next days, over a period of 8 days, the mice are treated with substance orally three times a day (7.00 h and 14.00 h and 19.00 h), two times a day (8.00 h and 18.00 h) or once a day (14.00 h). The daily dose is, for example 3 or 10 or 30 or 60 or 100 mg/kg of body weight, the volume administered is 10 ml/kg of body weight. The substances are formulated in the form of a 0.5% strength Tylose suspension with 2% DMSO or a 0.5% strength Tylose suspension. 9 days after transplantation and 16 hours after the last administration of substance, the animals are painlessly sacrificed and the sponge is removed. The virus-infected cells are released from the sponge by collagenase digestion (330 U/1.5 ml) and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO at −140° C. Evaluation takes place after serial ten-fold dilutions of the virus-infected cells by determining the titer on 24-well plates of confluent NHDF cells after vital staining with Neutral Red. The number of infected cells or infectious virus particles (infectious centre assay) after the substance treatment compared with the placebo-treated control is determined.
CYP Inhibition Assay
To investigate the mechanism-based (irreversible) inhibition of CYP3A4, different concentrations of the test substance are incubated with human liver microsomes (2 mg/ml of microsomal protein) in potassium phosphate buffer pH 7.4 with addition of an NADPH-generating system (NADP+, glucose 6-phosphate, glucose 6-phosphate dehydrogenase) at 37° C. At various points of time, 2 aliquots are taken from the incubation.
The first aliquot is incubated 1:50 in a new incubation solution (phosphate buffer, NADPH-generating system and 10 μM of Midazolam) at 37° C. for a further 10 min. The incubation is then stopped using acetonitrile on ice, the protein is pelleted in a centrifuge at 15 000 g and the supernatant is analysed for formation of 1′-hydroxyimidazolam using standard HPLC/MS methods.
The second aliquot is stopped using acetonitrile on ice and analysed for remaining test substance using HPLC/UV/MS.
The two sets of analytical data are determined for irreversible-inhibition-typical parameters (kinact, Ki and partition ratio r), and using these data, the test substance is evaluated (cf. A. Madan, et al., in A. D. Rodrigues (ed.) “Drug-Drug Interaction” in “Drugs and the Pharmaceutical Science”, Vol. 116, ISBN 0-8247-0283.2, Marcel Dekker Inc., New York, 2002.).
C. Exemplary Embodiments of Pharmaceutical Compositions
The compounds of the invention can be converted into pharmaceutical preparations in the following ways:
Tablet:
Composition:
100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Production:
The mixture of active ingredient, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water. The granules are then dried and mixed with the magnesium stearate for 5 min. This mixture is compressed using a conventional tablet press (see above for format of the tablet). A guideline for the compressive force used for the compression is 15 kN.
Suspension which can be Administered Orally:
Composition:
1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound of the invention.
Production:
The Rhodigel is suspended in ethanol, and the active ingredient is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.
Solution which can be Administered Intravenously:
Composition:
10-500 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.
Production:
The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterilized by filtration (pore diameter 0.22 μm) and dispensed under aseptic conditions into heat-sterilized infusion bottles. The latter are closed with infusion stoppers and trimmed caps.
Claims (27)
1. A compound of the formula
in which
Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and nitro,
where alkyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,
R1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl
R4 represents hydrogen or alkyl,
R5 represents hydrogen or alkyl
or
the radicals R4 and R5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups,
R6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro
and
R8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
or a salt, solvate, or solvate of a salt thereof.
2. A compound according to claim 1 , wherein
Ar represents phenyl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, carboxyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C1-C6-alkylamino and nitro,
R1 represents hydrogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-alkylthio, fluorine or chlorine,
R2 represents hydrogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-alkylthio, fluorine or chlorine,
R3 represents C1-C4-alkyl, cyano, fluorine, chlorine, nitro, trifluoromethyl or C1-C3-alkylsulphonyl,
R4 represents hydrogen or methyl,
R5 represents hydrogen,
R6 represents C1-C3-alkyl, C1-C3-alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,
R7 represents hydrogen, C1-C3-alkyl, C1-C3-alkoxy, fluorine, chlorine, cyano or hydroxyl
and
R8 represents hydrogen, C1-C3-alkyl, C1-C3-alkoxy, fluorine, chlorine, cyano or hydroxyl.
3. A compound according to claim 1 wherein
Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine,
R1 represents hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,
R2 represents hydrogen,
R3 represents methyl, isopropyl, tert-butyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
R4 represents hydrogen,
R5 represents hydrogen,
R6 represents aminocarbonyl, fluorine, chlorine, cyano or hydroxyl,
R7 represents hydrogen
and
R8 represents hydrogen, fluorine or chlorine.
4. A compound according to claim 1 , wherein R1 represents hydrogen, methyl, methoxy or fluorine.
5. A compound according to claim 1 , wherein R1 represents methoxy.
6. A compound according to claim 1 , wherein R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring.
7. A compound according to claim 1 , wherein R2 represents hydrogen.
8. A compound according to claim 1 , wherein R3 represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.
9. A compound according to claim 1 , wherein R3 represents trifluoromethyl, chlorine or methyl.
10. A compound according to claim 1 , wherein R1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring and R3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R1.
11. A compound according to claim 1 , wherein R4 and R5 represent hydrogen.
12. A compound according to claim 1 , wherein R6 represents fluorine.
13. A compound according to claim 1 , wherein R7 represents hydrogen.
14. A compound according to claim 1 , wherein R8 represents hydrogen, methyl or fluorine.
15. A compound according to claim 1 , wherein Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine.
16. A process for preparing a compound of the formula (I) according to claim 1 , wherein a compound of the formula
in which
Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1
and
R9 represents alkyl selected from the group consisting of methyl, ethyl, and tert-butyl,
is reacted with a base or an acid.
17. A medicament comprising a compound according to claim 1 in combination with an inert non-toxic pharmaceutically acceptable auxiliary.
18. A method for treating infection by Herpes viridae in humans and animals by administering an antivirally effective amount of at least one compound according to claim 1 , or a medicament according to claim 17 .
19. The method according to claim 18 , wherein the Heprpes viridae is selected form the group consisting of cytomegalovirus (CMV) and human cytomegalovirus (HCMV) or another representative of the group of the Herpes viridae.
20. A process for preparing a compound of formula (I) or a salt, solvate, or solvate of a salt thereof
in which
Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and nitro, where alkyl may be substituted by 1 to 3 substituents,
where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,
R1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl,
R4 represents hydrogen or alkyl,
R5 represents hydrogen or alkyl
or
the radicals R4 and R5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups,
R6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro, and
R8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
said process comprising:
(a) reacting a compound of formula (III)
wherein R6, R7, and R8 are as defined above and R9 is methyl or ethyl, in a two-step reaction initially with a compound of formula (IV)
21. The process according to claim 20, wherein said base is sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium carbonate, sodium carbonate or potassium carbonate.
22. The process according to claim 20, wherein said base is sodium hydroxide in water.
23. The process according to claim 20, wherein said inert solvent is 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or mixtures thereof.
24. The process according to claim 20, wherein said inert solvent is dioxane or tetrahydrofuran.
25. A process for preparing a compound of formula (I) or a salt, solvate, or solvate of a salt thereof
in which
Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and nitro, where alkyl may be substituted by 1 to 3 substituents,
where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,
R1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl,
R4 represents hydrogen or alkyl,
R5 represents hydrogen or alkyl
or
the radicals R4 and R5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups,
R6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro, and
R8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
said process comprising:
(a) reacting a compound of formula (III)
wherein R6, R7, and R8 are as defined above and R9 is methyl or ethyl, in a two-step reaction initially with a compound of formula (IV)
26. The process according to claim 25, wherein the reaction is carried out in a temperature range of from 0° C. to 40° C. at atmospheric pressure.
27. The process according to claim 25, wherein the acid is hydrogen chloride in dioxane, hydrogen bromide in acetic acid, or trifluoroacetic acid in methylene chloride.
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