TWI813680B - 新穎喹啉衍生物 - Google Patents
新穎喹啉衍生物 Download PDFInfo
- Publication number
- TWI813680B TWI813680B TW108116048A TW108116048A TWI813680B TW I813680 B TWI813680 B TW I813680B TW 108116048 A TW108116048 A TW 108116048A TW 108116048 A TW108116048 A TW 108116048A TW I813680 B TWI813680 B TW I813680B
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- TW
- Taiwan
- Prior art keywords
- alkyl
- group
- hydrogen
- alkoxy
- halogen atoms
- Prior art date
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- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title abstract description 3
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 350
- 238000000034 method Methods 0.000 claims abstract description 101
- 238000011282 treatment Methods 0.000 claims abstract description 35
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 claims abstract description 27
- 208000006968 Helminthiasis Diseases 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 230000006806 disease prevention Effects 0.000 claims abstract description 10
- -1 3-fluoroazetidin-1-yl Chemical group 0.000 claims description 243
- 229910052739 hydrogen Inorganic materials 0.000 claims description 208
- 239000001257 hydrogen Substances 0.000 claims description 205
- 125000005843 halogen group Chemical group 0.000 claims description 134
- 239000000203 mixture Substances 0.000 claims description 134
- 150000003839 salts Chemical class 0.000 claims description 122
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 85
- 229910052736 halogen Inorganic materials 0.000 claims description 76
- 150000002367 halogens Chemical class 0.000 claims description 73
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 65
- 150000001204 N-oxides Chemical class 0.000 claims description 61
- 229910052731 fluorine Inorganic materials 0.000 claims description 53
- 150000004677 hydrates Chemical class 0.000 claims description 53
- 239000000460 chlorine Substances 0.000 claims description 51
- 229910052801 chlorine Inorganic materials 0.000 claims description 51
- 239000011737 fluorine Substances 0.000 claims description 51
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 47
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 46
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 37
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 22
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical group COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- WQYAZBFZFIUIPL-UHFFFAOYSA-N 3-fluoroazetidine Chemical compound FC1CNC1 WQYAZBFZFIUIPL-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 39
- ZOAMZFNAPHWBEN-UHFFFAOYSA-N 2-$l^{1}-oxidanylpropane Chemical group CC(C)[O] ZOAMZFNAPHWBEN-UHFFFAOYSA-N 0.000 claims 1
- 239000001273 butane Substances 0.000 claims 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 29
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000012453 solvate Substances 0.000 description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- 239000000543 intermediate Chemical class 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- 239000002253 acid Substances 0.000 description 44
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 229940060038 chlorine Drugs 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 31
- 239000002585 base Substances 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 26
- 238000012360 testing method Methods 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 230000002496 gastric effect Effects 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 229910052805 deuterium Inorganic materials 0.000 description 23
- 235000019253 formic acid Nutrition 0.000 description 23
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 22
- 150000002148 esters Chemical class 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- 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 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- 208000000291 Nematode infections Diseases 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 230000000507 anthelmentic effect Effects 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 10
- 230000000155 isotopic effect Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 241000243988 Dirofilaria immitis Species 0.000 description 9
- 241000244206 Nematoda Species 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000002207 metabolite Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 239000003643 water by type Substances 0.000 description 9
- 239000004215 Carbon black (E152) Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 229940099686 dirofilaria immitis Drugs 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 244000000013 helminth Species 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 7
- 108010022752 Acetylcholinesterase Proteins 0.000 description 7
- 102000012440 Acetylcholinesterase Human genes 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 229940022698 acetylcholinesterase Drugs 0.000 description 7
- 239000000921 anthelmintic agent Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- OQIYMHFTXQTJBV-UHFFFAOYSA-N ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate Chemical compound BrC=1C(=CC=C2C(=C(C=NC=12)C(=O)OCC)Cl)F OQIYMHFTXQTJBV-UHFFFAOYSA-N 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAKOZHOLGAGEJT-UHFFFAOYSA-N 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)-Ethane Chemical compound C1=CC(OC)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(OC)C=C1 IAKOZHOLGAGEJT-UHFFFAOYSA-N 0.000 description 6
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 241000238421 Arthropoda Species 0.000 description 6
- 101100421668 Caenorhabditis elegans slo-1 gene Proteins 0.000 description 6
- 231100000491 EC50 Toxicity 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940124339 anthelmintic agent Drugs 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000003120 macrolide antibiotic agent Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 6
- ZOCSXAVNDGMNBV-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound NC1=C(S(=O)C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl ZOCSXAVNDGMNBV-UHFFFAOYSA-N 0.000 description 5
- DHQKLWKZSFCKTA-UHFFFAOYSA-N ClC1=CC=C(C=N1)CN1C(C=CC=C1)=NC(C(F)(F)F)=O Chemical compound ClC1=CC=C(C=N1)CN1C(C=CC=C1)=NC(C(F)(F)F)=O DHQKLWKZSFCKTA-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
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- 241000282412 Homo Species 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
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- 125000003118 aryl group Chemical group 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
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- NYPJDWWKZLNGGM-UHFFFAOYSA-N fenvalerate Aalpha Natural products C=1C=C(Cl)C=CC=1C(C(C)C)C(=O)OC(C#N)C(C=1)=CC=CC=1OC1=CC=CC=C1 NYPJDWWKZLNGGM-UHFFFAOYSA-N 0.000 description 5
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- 230000002503 metabolic effect Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
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- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- DBHVHTPMRCXCIY-UHFFFAOYSA-N tyclopyrazoflor Chemical compound N1=C(Cl)C(N(C(=O)CCSCCC(F)(F)F)CC)=CN1C1=CC=CN=C1 DBHVHTPMRCXCIY-UHFFFAOYSA-N 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- 239000005660 Abamectin Substances 0.000 description 4
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- 125000002053 thietanyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- BAKXBZPQTXCKRR-UHFFFAOYSA-N thiodicarb Chemical compound CSC(C)=NOC(=O)NSNC(=O)ON=C(C)SC BAKXBZPQTXCKRR-UHFFFAOYSA-N 0.000 description 1
- OPASCBHCTNRLRM-UHFFFAOYSA-N thiometon Chemical compound CCSCCSP(=S)(OC)OC OPASCBHCTNRLRM-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 1
- QSOHVSNIQHGFJU-UHFFFAOYSA-L thiosultap disodium Chemical compound [Na+].[Na+].[O-]S(=O)(=O)SCC(N(C)C)CSS([O-])(=O)=O QSOHVSNIQHGFJU-UHFFFAOYSA-L 0.000 description 1
- 229940074152 thuringiensin Drugs 0.000 description 1
- IHNSIFFSNUQGQN-UHFFFAOYSA-N tioxazafen Chemical compound C1=CSC(C=2ON=C(N=2)C=2C=CC=CC=2)=C1 IHNSIFFSNUQGQN-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- WPALTCMYPARVNV-UHFFFAOYSA-N tolfenpyrad Chemical compound CCC1=NN(C)C(C(=O)NCC=2C=CC(OC=3C=CC(C)=CC=3)=CC=2)=C1Cl WPALTCMYPARVNV-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- YWSCPYYRJXKUDB-KAKFPZCNSA-N tralomethrin Chemical compound CC1(C)[C@@H](C(Br)C(Br)(Br)Br)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 YWSCPYYRJXKUDB-KAKFPZCNSA-N 0.000 description 1
- DDVNRFNDOPPVQJ-HQJQHLMTSA-N transfluthrin Chemical compound CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)OCC1=C(F)C(F)=CC(F)=C1F DDVNRFNDOPPVQJ-HQJQHLMTSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QCRXMFTZTSTGJM-UHFFFAOYSA-N triacetyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CC(=O)OC(=O)CC(O)(C(=O)OC(C)=O)CC(=O)OC(C)=O QCRXMFTZTSTGJM-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- JWXZLCFGVKMEEK-UHFFFAOYSA-N triarathene Chemical compound C1=CC(Cl)=CC=C1C1=CC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)S1 JWXZLCFGVKMEEK-UHFFFAOYSA-N 0.000 description 1
- NKNFWVNSBIXGLL-UHFFFAOYSA-N triazamate Chemical compound CCOC(=O)CSC1=NC(C(C)(C)C)=NN1C(=O)N(C)C NKNFWVNSBIXGLL-UHFFFAOYSA-N 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- AMFGTOFWMRQMEM-UHFFFAOYSA-N triazophos Chemical compound N1=C(OP(=S)(OCC)OCC)N=CN1C1=CC=CC=C1 AMFGTOFWMRQMEM-UHFFFAOYSA-N 0.000 description 1
- XOIOGKHKNQYULW-HTNNXBMUSA-N tribendimidine Chemical compound C1=CC(/N=C(\C)N(C)C)=CC=C1\N=C\C(C=C1)=CC=C1\C=N\C1=CC=C(\N=C(/C)N(C)C)C=C1 XOIOGKHKNQYULW-HTNNXBMUSA-N 0.000 description 1
- KVSKGMLNBAPGKH-UHFFFAOYSA-N tribromosalicylanilide Chemical compound OC1=C(Br)C=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 KVSKGMLNBAPGKH-UHFFFAOYSA-N 0.000 description 1
- 229950001807 tribromsalan Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960000323 triclabendazole Drugs 0.000 description 1
- UGCNRZFAUBJVPT-UHFFFAOYSA-N tricyclohexyltin;hydrate Chemical compound O.C1CCCCC1[Sn](C1CCCCC1)C1CCCCC1 UGCNRZFAUBJVPT-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Tropical Medicine & Parasitology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
本發明涵蓋通式(I)之新穎喹啉化合物:,
其中A、R1
、R2
、R3
、R4
、R5
、R6
及Q如本文所定義,製備該等化合物之方法,適用於製備該等化合物之中間化合物,包含該等化合物之醫藥組合物及組合,及該等化合物作為單一藥劑或與其他活性成分組合用於製造用以治療、控制及/或預防疾病,特定言之蠕蟲感染之醫藥組合物的用途。
Description
本發明涵蓋如本文所描述及定義之通式(I)之新穎喹啉衍生物;製備該等化合物之方法;適用於製備該等化合物之中間化合物;包含該等化合物之醫藥組合物及組合;及該等化合物作為單一藥劑或與其他活性成分組合用於製造醫藥組合物之用途,該等醫藥組合物用以控制、治療及/或預防疾病,特定言之用以控制、治療及/或預防動物及人類之蠕蟲感染,更特定言之胃腸及腸外線蟲感染;含有此類化合物之調配物及用於控制、治療及/或預防動物及人類之蠕蟲感染,更特定言之胃腸及腸外線蟲感染之方法。
對所有市售驅蠕蟲劑出現抗性似乎為獸醫學領域中日益嚴重的問題。廣泛使用驅蠕蟲劑管理控制線蟲導致對高抗性蠕蟲群體具有顯著選擇效應。因此,對所有驅蠕蟲藥物類別具有抗性之蔓延威脅到了牛、山羊、綿羊及馬中之有效蠕蟲控制。此外,目前僅依賴於使用巨環內酯的犬絲蟲病之成功預防存在危險,因為在美利堅合眾國之一些區域,尤其在絲蟲攻擊感染高發之區域中已描述多種巨環內酯有功效損失。最終,用來自密西西比三角洲下游(the Lower Mississippi Delta)之疑似功效損失病例之犬惡絲蟲(Dirofilaria immitis
)幼蟲進行之實驗性感染研究在活體內確認存在巨環內酯抗性。
儘管人類蠕蟲對驅蠕蟲劑之抗性目前似乎罕見,但在人類蠕蟲病之治療中亦需要考慮如上文所提及之獸醫學領域中驅蠕蟲抗性之蔓延。對絲蟲病之持久性劑量不足的治療可產生高抗性基因型且已描述對某些驅蠕蟲劑(例如吡喹酮、苯并咪唑及氯硝柳胺)有抗性。
因此,迫切需要具有新穎分子作用模式之阻抗性驅蠕蟲劑。
本發明之目的為提供可在醫學,尤其獸醫學領域中可用作驅蠕蟲劑,特定言之在相對低劑量下對廣泛範圍之蠕蟲具有令人滿意或改良之驅蠕蟲活性,用於控制、治療及/或預防動物及人類之蠕蟲感染,較佳對治療之生物體無任何不良毒性效應之化合物。
某些喹啉甲醯胺作為適用於治療及/或預防如尋常痤瘡、皮膚炎或其類似疾病之皮膚病之藥劑描述於JP2008-214323A中。
WO2017103851揭示適用於治療動脈粥樣硬化、牛皮癬、鼻竇炎及杜興氏肌肉萎縮症(duchenne muscular dystrophy)之作為H-PGDS抑制劑之喹啉-3-甲醯胺。
WO2018087036揭示在醫學,尤其獸醫學領域作為驅蠕蟲劑之喹啉-3-甲醯胺。
然而,現有技術水平並未描述如本文所描述及定義之本發明之通式(I)之新穎喹啉衍生物。
現已發現,本發明之化合物具有出人意料且有利之特性,且此構成本發明之基礎。
特定言之,已出人意料地發現本發明化合物與線蟲之Slo-1鈣閘控鉀通道有效地相互作用。此相互作用之特徵在於實現特定言之胃腸線蟲、自由活線蟲及絲蟲之麻痹/抑制,其資料在生物學實驗部分中給出。因此,本發明化合物可用作用於控制、治療及/或預防胃腸及腸外蠕蟲感染,特定言之胃腸及腸外線蟲感染(包括絲蟲)感染之驅蠕蟲劑。
根據第一態樣,本發明涵蓋通式(I)之化合物:
其中:
A 為A1或A2,
o 為0、1、2、3或4,
R 選自由以下組成之群:氫、鹵素、氰基、硝基、-OH、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C3
-C6
環烷基、-NH2
、-NH(C1
-C4
烷基)、 -N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、 -S-C1
-C4
鹵代烷基、-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O、S及N-R9
,其中X及Y中之至少一者為CR7
R8
,或
X、Y 一起形成選自由以下組成之群的環成員:-C(O)-O-、-C(O)-NR9
-、-S(O)-NR9
-、-SO2
-NR9
-及-SO2
-O-,
R1
選自由以下組成之群:氫、氰基、-CHO、-OH、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C3
-C6
環烷基、具有1至5個鹵素原子之C3
-C6
鹵代環烷基、C3
-C4
烯基、C3
-C4
炔基、C1
-C4
烷氧基-C1
-C4
烷基、C3
-C6
環烷基-C1
-C3
烷基、氰基-C1
-C4
烷基、-NH-C1
-C4
烷基、-N(C1
-C4
烷基)2
、NH2
-C1
-C4
烷基-、C1
-C4
烷基-NH-C1
-C4
烷基-、(C1
-C4
烷基)2
N-C1
-C4
烷基-、C1
-C4
烷基-C(O)-、具有1至5個鹵素原子之C1
-C4
鹵代烷基-C(O)-、C1
-C4
烷氧基-C(O)-、苯甲氧基-C(O)-、C1
-C4
烷氧基-C1
-C4
烷基-C(O)-、-SO2
-C1
-C4
烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基;
苯基-C1
-C4
烷基,其視情況經獨立地選自由以下組成之群中的1、2、3、4或5個取代基取代:鹵素、-OH、-NO2
、氰基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、 -S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、具有1至5個鹵素原子之-S-C1
-C4
鹵代烷基、具有1至5個鹵素原子之-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基;
雜環基-C1
-C4
烷基,其中雜環基取代基選自由以下組成之群:4員至10員雜環烷基、5員雜芳基及6員雜芳基,其中之每一者視情況經獨立地選自由以下組成之群中的1、2或3個取代基取代:鹵素、-OH、-NO2
、氰基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、具有1至5個鹵素原子之-S-C1
-C4
鹵代烷基、具有1至5個鹵素原子之-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或C1
-C4
烷基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、C3
-C6
環烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基 -C1
-C4
烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C1
-C4
烷基-C(O)-、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、C3
-C6
環烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基-C1
-C4
烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C1
-C4
烷基-C(O)-、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基,
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、C3
-C6
環烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基-C1
-C4
烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C1
-C4
烷基-C(O)-、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基,
R7
選自由以下組成之群:氫、-OH、氟、C1
-C4
烷基及C1
-C4
烷氧基,
R8
選自由以下組成之群:氫、-OH、氟、C1
-C4
烷基及C1
-C4
烷氧基,
或R7
及R8
一起形成側氧基(=O),
或R7
及R8
連同其所連接之碳原子一起形成3員至6員環,該環選自由以下組成之群:C3
-C6
環烷基及3員至6員雜環烷基,
R9
選自由以下組成之群:氫、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基及C1
-C4
烷氧基,
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,
R11
選自由以下組成之群:氫、C1
-C4
烷基及C1
-C4
烷氧基,
或R10
及R11
連同其所連接之碳原子一起形成3員至6員環,該環選自由以下組成之群:C3
-C6
環烷基及3員至6員雜環烷基,
Q 為2,3,5-三氟苯基,
其中當Y為O、S或N-R9
時,R7
、R8
、R10
及R11
中無一者為-OH或C1
-C4
烷氧基,且其中當X為O、S或N-R9
時,R7
及R8
中無一者為-OH或C1
-C4
烷氧基;
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
定義
術語「經取代」意謂指定原子或基團上之一或多個氫原子經來自指定基團之選擇置換,其限制條件為不超過現有情形下指定原子之正常原子價。容許取代基及/或變數之組合。
術語「視情況經取代」意謂取代基之數目可等於或不等於零。除非另外指明,否則視情況經取代之基團有可能經許多視情況存在之取代基取代,只要該等取代基可藉由在任何可用碳或氮原子上用非氫取代基置換氫原子來容納即可。通常,視情況存在之取代基(若存在)的數目有可能為1、2、3、4或5,尤其1、2或3。
如本文所使用,術語「一或多個」,例如在本發明之通式(I)化合物之取代基之定義中,意謂「1、2、3、4或5個,特定言之1、2、3或4個,更特定言之1、2或3個,甚至更特定言之1或2個」。
如本文所用,側氧基取代基表示經由雙鍵鍵結至碳原子或硫原子之氧原子。
術語「環取代基」意謂連接至芳環或非芳環之取代基,其置換該環上之可用氫原子。
若複合取代基由超過一個部分組成,例如(C1
-C4
烷氧基) -(C1
-C4
烷基)-,則給定部分之位置有可能在該複合取代基之任何適合之位置處,亦即C1
-C4
烷氧基部分可經連接至該(C1
-C4
烷氧基)-(C1
-C4
烷基)-基團之C1
-C4
烷基部分之任一碳原子。此複合取代基之開頭或末尾處之連字符指示該複合取代基與分子之其餘部分之連接點。若包含碳原子及視情況存在之一或多個雜原子(諸如氮、氧或硫原子)之環例如經取代基取代,則該取代基有可能在該環之任何適合位置處鍵結,其鍵結至適合碳原子及/或適合雜原子。
如本文中所使用,各別取代基連接至分子之其餘部分的位置可在繪製之結構中藉由該取代基中之井號(#)或虛線描述。
術語「包含(comprising)」在用於本說明書中時包括「由……組成(consisting of)」。
若在本發明文本內任何項目稱為「如本文所提及」,則其意謂其可在本發明文本中之任何位置提及。
如本發明文本中所提及之術語具有以下含義:
術語「鹵素原子」意謂氟、氯、溴或碘原子,特定言之氟、氯或溴原子。
術語「C1
-C6
烷基」意謂具有1、2、3、4、5或6個碳原子之直鏈或分支鏈、飽和、單價烴基。術語「C1
-C4
烷基」意謂具有1、2、3或4個碳原子之直鏈或分支鏈、飽和、單價烴基,例如甲基、乙基、正丙基、
異丙基、正丁基、第二丁基、異丁基或第三丁基或其異構體。特定言之,該基團具有1、2或3個碳原子(「C1
-C3
烷基」),例如甲基、乙基、正丙基或異丙基。
術語「C1
-C4
羥基烷基」意謂直鏈或分支鏈、飽和、單價烴基,其中術語「C1
-C4
烷基」如上文所定義,且其中1或2個氫原子經羥基置換,例如羥基甲基、1-羥基乙基、2-羥基乙基、1,2-二羥基乙基、3-羥丙基、2-羥丙基、1-羥丙基、1-羥基丙-2-基、2-羥基丙-2-基、2,3-二羥丙基、1,3-二羥基丙-2-基、3-羥基-2-甲基-丙基、2-羥基-2-甲基-丙基、1-羥基-2-甲基-丙基。
術語「-NH(C1
-C4
烷基)」或「-N(C1
-C4
烷基)2
」意謂直鏈或分支鏈、飽和、單價基團,其中術語「C1
-C4
烷基」如上文所定義,例如甲胺基、乙胺基、正丙胺基、異丙胺基、N,N-
二甲胺基、N-
甲基-N-
乙胺基或N,N-
二乙胺基。
術語「-S-C1
-C4
烷基」、「-S(O)-C1
-C4
烷基」或「-SO2
-C1
-C4
烷基」意謂直鏈或分支鏈飽和基團,其中術語「C1
-C4
烷基」如上文所定義,例如甲基硫基、乙基硫基、正丙基硫基、異丙基硫基、正丁基硫基、第二丁基硫基、異丁基硫基或第三丁基硫基、甲基亞磺醯基、乙基亞磺醯基、正丙基亞磺醯基、異丙基亞磺醯基、正丁基亞磺醯基、第二丁基亞磺醯基、異丁基亞磺醯基或第三丁基亞磺醯基、或甲基磺醯基、乙基磺醯基、正丙基磺醯基、異丙基磺醯基、正丁基磺醯基、第二丁基磺醯基、異丁基磺醯基或第三丁基磺醯基。
術語「C1
-C4
鹵烷基」意謂直鏈或分支鏈、飽和單價烴基,其中術語「C1
-C4
烷基」如上文所定義,且其中氫原子中之一或多者經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟原子。更特定言之,所有該等鹵素原子為氟原子(「C1
-C4
氟烷基」)。該C1
-C4
鹵代烷基為例如氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基或1,3-二氟丙-2-基。
術語「C1
-C4
烷氧基」意謂式(C1
-C4
烷基)-O-之直鏈或分支鏈、飽和單價基團,其中術語「C1
-C4
烷基」如上文所定義,例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、異丁氧基或第三丁氧基,或其異構體。
術語「C1
-C4
鹵代烷氧基」意謂如上文所定義之直鏈或分支鏈、飽和單價C1
-C4
烷氧基,其中氫原子中之一或多者經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟原子。該C1
-C4
鹵代烷氧基為例如氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基或五氟乙氧基。
術語「C2
-C4
烯基」意謂直鏈或分支鏈的單價烴基,其含有一個雙鍵,且其具有2、3或4個碳原子。該C2
-C4
烯基為例如乙烯基(ethenyl) (或「乙烯基(vinyl)」)、丙-2-烯-1-基(或「烯丙基」)、丙-1-烯 -1-基、丁-3-烯基、丁-2-烯基、丁-1-烯基、丙-1-烯-2-基(或「異丙烯基」)、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基或1-甲基丙-1-烯基。特定言之,該基團為烯丙基。
術語「C2
-C4
炔基」意謂含有一個三鍵且含有2、3或4個碳原子之直鏈單價烴基。該C2
-C4
炔基為例如乙炔基、丙-1-炔基、丙-2-炔基(或「炔丙基」)、丁-1-炔基、丁-2-炔基、丁-3-炔基或1-甲基丙-2-炔基。特定言之,該炔基為丙-1-炔基或丙-2-炔基。
術語「C3
-C6
環烷基」意謂含有3、4、5或6個碳原子之飽和的單價單環烴環(「C3
-C6
環烷基」)。該C3
-C6
環烷基為例如單環烴環,例如環丙基、環丁基、環戊基或環己基。
術語「C3
-C6
鹵代環烷基」意謂飽和的單價單環烴環,其中術語「C3
-C6
環烷基」如上文所定義,且其中氫原子中之一或多者經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟或氯原子。該C3
-C6
鹵代環烷基為例如經一或兩個氟或氯原子取代之單環烴環,例如1-氟-環丙基、2-氟環丙基、2,2-二氟環丙基、2,3-二氟環丙基、1-氯環丙基、2-氯環丙基、2,2-二氯環丙基、2,3-二氯環丙基、2-氟-2-氯環丙基及2-氟 -3-氯環丙基。
術語「苯并-C5
-C6
環烷基」意謂其中含有5或6個碳原子之飽和的單價單環烴環(「C5
-C6
環烷基」)與苯環并環的單價雙環烴環。該苯并-C5
-C6
環烷基為例如雙環烴環,例如茚滿(亦即2,3-二氫-1H-茚)或萘滿(亦即1,2,3,4-四氫化萘)。
術語「螺環烷基」意謂飽和的單價雙環烴基,其中兩個環共有一個共同環碳原子,且其中該雙環烴基含有5、6、7、8、9、10或11個碳原子,該螺環烷基有可能經由除螺碳原子以外之任一碳原子連接至分子之其餘部分。該螺環烷基為例如螺[2.2]戊基、螺[2.3]己基、螺[2.4]庚基、螺[2.5]辛基、螺[2.6]壬基、螺[3.3]庚基、螺[3.4]辛基、螺[3.5]壬基、螺[3.6]癸基、螺[4.4]壬基、螺[4.5]癸基、螺[4.6]十一基或螺[5.5]十一基。
術語「雜環烷基」意謂具有總計4、5、6、7、8、9或10個環原子(「4員至10員雜環烷基」),特定言之4、5或6個環原子(「4員至6員雜環烷基」)之單環或雙環的飽和或部分飽和雜環基,其含有一個或兩個與系列N、O及S相同或不同環雜原子,該雜環烷基可能經由碳原子中之任一者或(若存在)氮原子而連接至分子之其餘部分。
該雜環烷基可為(但不限於)4員環,諸如氮雜環丁烷基、氧雜環丁烷基或硫雜環丁基;或5員環,諸如四氫呋喃基、氧雜環戊基、1,3-二氧雜環戊烷基、硫雜環戊烷基、吡咯啶基、咪唑啶基、吡唑啶基、1,1-二氧離子基硫雜環戊烷基、1,2-噁唑啶基、1,3-噁唑啶基、1,3-噻唑啶基或1,2,4-三唑啶基;或6員環,諸如四氫哌喃基、四氫硫哌喃基、哌啶基、嗎啉基、二噻烷基、硫代嗎啉基、哌嗪基、氧雜環己基、1,3-二氧雜環己烷基、1,4-二氧雜環己烷基或1,2-氧氮雜環己烷基;或7員環,諸如氮雜環庚烷基、1,4-二氮雜環庚烷基或1,4-氧氮雜環庚烷基;或雙環7員環,諸如6-氧雜-3-氮雜雙環[3.1.1]庚;或雙環8員環,諸如5,6-二氫-4H-呋喃并[2,3-c]吡咯或8-氧雜-3-氮雜雙環[3.2.1]辛;或雙環9-員環,諸如八氫 -1H-吡咯并[3,4-b]吡啶、1,3-二氫-異吲哚、2,3-二氫-吲哚或3,9-二氧雜 -7-氮雜雙環[3.3.1]壬;或雙環10員環,諸如十氫喹琳或3,4-二氫異喹啉。
術語「雜螺環烷基」意謂總計具有6、7、8、9、10或11個環原子之雙環飽和雜環,其中兩個環共有一個共同環碳原子,該「雜螺環烷基」含有一個或兩個來自系列N、O、S之相同或不同環雜原子;該雜螺環烷基有可能經由除螺碳原子以外之碳原子中之任一者或氮原子(若存在)連接至分子之其餘部分。
該雜螺環烷基為例如氮雜螺[2.3]己基、氮雜螺[3.3]庚基、氧雜氮雜螺[3.3]庚基、硫雜氮雜螺[3.3]庚基、氧雜螺[3.3]庚基、氧雜氮雜螺[5.3]壬基、氧雜氮雜螺[4.3]辛基、氧雜氮雜螺[2.5]辛基、氮雜螺[4.5]癸基、氧雜氮雜螺[5.5]十一烷基、二氮雜螺[3.3]庚基、硫雜氮雜螺[3.3]庚基、硫雜氮雜螺[4.3]辛基、氮雜螺[5.5]十一烷基或其他同源架構中之一者,諸如螺[3.4]-、螺[4.4]-、螺[2.4]-、螺[2.5]-、螺[2.6]-、螺[3.5]-、螺[3.6]-、螺[4.5]-及螺[4.6]-。
術語「6員或10員芳基」意謂具有6或10個碳環原子之單價地單環或雙環芳環,例如苯基或萘基。
術語「雜芳基」意謂具有5、6、9或10個環原子(「5至10員雜芳基」)、特定言之5或6個環原子(「5至6員雜芳基」)之單價單環、雙環或三環芳族環,其含有至少一個環雜原子及視情況存在之一個、兩個或三個來自系列N、O及/或S之其他環雜原子且其經由環碳原子或視情況經由環氮原子(若原子價允許)鍵結。
該雜芳基可為5員雜芳基,諸如噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、異噻唑基、噁二唑基、三唑基、噻二唑基或四唑基;或6員雜芳基,諸如吡啶基、二氫吡啶基、噠嗪基、嘧啶基、四氫嘧啶基、吡嗪基或三嗪基。
術語「雜環基」意謂選自由雜環烷基及雜芳基組成之群的雜環基。特定言之,術語「4員至6員雜環基」意謂選自由以下組成之群的雜環基:4員至6員雜環烷基及5員至6員雜芳基。
一般而言,且除非另有提及,否則雜芳基或伸雜芳基包括其所有可能的異構體形式,例如相對於分子之其餘部分之連接點之互變異構體及位置異構體。因此,對於一些說明性非限制性實例,術語吡啶基包括吡啶-2-基、吡啶-3-基及吡啶-4-基;或術語噻吩基包括噻吩-2-基及噻吩-3-基。
如本發明文本中所用,例如在「C1
-C4
烷基」、「C1
-C4
鹵代烷基」、「C1
-C4
羥基烷基」、「C1
-C4
烷氧基」或「C1
-C4
鹵代烷氧基」之定義的上下文中,術語「C1
-C4
」意謂具有1至4個有限數目之碳原子,亦即1、2、3或4個碳原子之烷基。
另外,如本發明文本中所用,例如在「C3
-C6
環烷基」或C3
-C6
鹵代環烷基之定義的上下文中,術語「C3
-C6
」意謂具有3至6個有限數目之碳原子,亦即3、4、5或6個碳原子之環烷基。
當給定值之範圍時,該範圍涵蓋該範圍內之各值及子範圍。
舉例而言:
「C1
-C4
」涵蓋C1
、C2
、C3
、C4
、C1
-C4
、C1
-C3
、C1
-C2
、C2
-C4
、C2
-C3
及C3
-C4
;
「C2
-C6
」涵蓋C2
、C3
、C4
、C5
、C6
、C2
-C6
、C2
-C5
、C2
-C4
、C2
-C3
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C6
、C4
-C5
及C5
-C6
;
「C3
-C4
」涵蓋C3
、C4
及C3
-C4
;
「C3
-C10
」涵蓋C3
、C4
、C5
、C6
、C7
、C8
、C9
、C10
、C3
-C10
、C3
-C9
、C3
-C8
、C3
-C7
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C10
、C4
-C9
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C10
、C5
-C9
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
;
「C3
-C8
」涵蓋C3
、C4
、C5
、C6
、C7
、C8
、C3
-C8
、C3
-C7
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C8
、C6
-C7
及C7
-C8
;
「C3
-C6
」涵蓋C3
、C4
、C5
、C6
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C6
、C4
-C5
及C5
-C6
;
「C4
-C8
」涵蓋C4
、C5
、C6
、C7
、C8
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C8
、C6
-C7
及C7
-C8
;
「C4
-C7
」涵蓋C4
、C5
、C6
、C7
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C7
、C5
-C6
及C6
-C7
;
「C4
-C6
」涵蓋C4
、C5
、C6
、C4
-C6
、C4
-C5
及C5
-C6
;
「C5
-C10
」涵蓋C5
、C6
、C7
、C8
、C9
、C10
、C5
-C10
、C5
-C9
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
;
「C6
-C10
」涵蓋C6
、C7
、C8
、C9
、C10
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
。
如本文所用,術語「脫離基」意謂在化學反應中經置換為帶有鍵結電子之穩定物種的原子或原子基團。特定言之,此脫離基選自包含以下之群:鹵化物、特定言之氟、氯、溴或碘,(甲磺醯基)氧基、[(三氟甲基)磺醯基]氧基、[(九氟丁基)磺醯基]氧基、(苯磺醯基)氧基、[(4-甲基苯基)磺醯基]氧基、[(4-溴苯基)磺醯基]氧基、[(4-硝基苯基)磺醯基]氧基、[(2-硝苯)磺醯基]氧基、[(4-異丙基苯基)磺醯基]氧基、[(2,4,6-三異丙基苯基)磺醯基]氧基、[(2,4,6-三甲基苯基)磺醯基]氧基、[(4-第三丁基苯基)磺醯基]氧基及[(4-甲氧基苯基)磺醯基]氧基。
在本發明上下文中之側氧基取代基意謂經由雙鍵鍵結至碳原子之氧原子。
通式(I)化合物有可能以同位素變體之形式存在。因此,本發明包括通式(I)化合物之一或多個同位素變體,特定言之含氘之通式(I)化合物。
術語化合物或試劑之「同位素變體」定義為具有非天然比例的構成此類化合物之同位素中之一或多者的化合物。
術語「通式(I)化合物之同位素變體」定義為具有非天然比例的構成此類化合物之同位素中之一或多者的通式(I)化合物。
表述「非天然比例」意謂此類同位素高於其天然豐度之比例。此上下文中應用之同位素之天然豐度描述於「Isotopic Compositions of the Elements 1997」, Pure Appl. Chem., 70(1), 217-235, 1998中。
此類同位素之實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之穩定的放射性同位素,分別諸如2
H (氘)、3
H (氚)、11
C、13
C、14
C、15
N、17
O、18
O、32
P、33
P、33
S、34
S、35
S、36
S、18
F、36
Cl、82
Br、123
I、124
I、125
I、129
I及131
I。
關於本文中所指定病症之治療及/或預防,通式(I)化合物之同位素變體較佳含有氘(「含氘之通式(I)化合物」)。其中併入一或多個放射性同位素,諸如3
H或14
C之通式(I)化合物之同位素變異體適用於例如藥物及/或基質組織分佈研究。出於其併入及可偵測之便利,此等同位素為尤其較佳的。諸如18
F或11
C之正電子發射同位素可併入通式(I)化合物中。通式(I)化合物之此等同位素變體適用於活體內成像應用。含氘及含13
C之通式(I)化合物可在臨床前或臨床研究之情形下用於質譜分析中。
通式(I)化合物之同位素變體通常可藉由熟習此項技術者已知之方法製備,諸如本文流程及/或實例中所述之方法,藉由用一試劑之同位素變體、較佳含氘試劑取代該試劑。視所期望的氘化位點而定,在一些情況下,可將來自D2
O之氘直接併入化合物中或併入適用於合成此類化合物之試劑中。氘氣亦為適用於將氘併入分子中之試劑。烯鍵及炔鍵之催化氘化為併入氘之快速途徑。在氘氣存在下,金屬催化劑(亦即Pd、Pt及Rh)可用於將含有烴之官能基中的氫直接交換為氘。多種氘化試劑及合成結構單元可購自諸如以下公司:C/D/N Isotopes, Quebec, Canada;Cambridge Isotope Laboratories Inc., Andover, MA, USA;及CombiPhos Catalysts, Inc., Princeton, NJ, USA。
術語「含氘之通式(I)化合物」定義為其中一或多個氫原子經一或多個氘原子置換且其中通式(I)化合物之各氘化位置處之氘豐度高於氘之天然豐度(其為約0.015%)的通式(I)化合物。特定言之,在含氘之通式(I)化合物中,通式(I)化合物之各氘化位置處之氘豐度高於10%、20%、30%、40%、50%、60%、70%或80%,較佳地高於90%、95%、96%或97%,甚至更佳地在該位置處高於98%或99%。應瞭解,各氘化位置處之氘豐度與其他氘化位置處之氘豐度無關。
將一或多個氘原子選擇性併入通式(I)化合物中可改變分子之物理化學特性(諸如酸性[C. L. Perrin等人, J. Am. Chem. Soc., 2007, 129, 4490]、鹼性[C. L. Perrin等人, J. Am. Chem. Soc., 2005, 127, 9641]、親脂性[B. Testa等人, Int. J. Pharm., 1984, 19(3), 271])及/或代謝概況,且可引起母化合物與代謝物之比率或所形成代謝物之量變化。此類改變可產生某些治療優勢且因此在一些情況下可為較佳的。已報導代謝及代謝轉換之速率降低,其中代謝物比率經改變(A. E. Mutlib等人, Toxicol. Appl. Pharmacol., 2000, 169, 102)。在暴露於母藥物及代謝物時之此等改變可具有關於含氘之通式(I)化合物之藥效學、耐受性及功效之重要結果。在一些情況下,氘取代減少或消除非所要或毒性代謝物之形成且促進所要代謝物之形成(例如,奈韋拉平(Nevirapine):A. M. Sharma等人,Chem. Res. Toxicol., 2013, 26, 410;依法韋侖(Efavirenz):A. E. Mutlib等人,Toxicol. Appl. Pharmacol., 2000, 169, 102)。在其他情況下,氘化之主要作用為降低全身清除率。因而,增加化合物之生物半衰期。潛在臨床益處包括能夠藉由降低峰值水準及增加谷值水準來維持類似的全身暴露。此舉可視特定化合物之藥物動力學/藥效學關係而定,減少副作用且增強功效。ML-337 (C. J. Wenthur等人, J. Med. Chem., 2013, 56, 5208)及奧當卡替(Odanacatib) (K. Kassahun等人, WO2012/112363)為此氘作用之實例。另外報導有其他情況,其中代謝速率降低導致藥物之暴露量增加而未改變全身清除率(例如羅非考昔(Rofecoxib):F. Schneider等人,Arzneim. Forsch./Drug. Res., 2006, 56, 295;特拉匹韋(Telaprevir):F. Maltais等人,J. Med. Chem., 2009, 52, 7993)。展示此作用之氘化藥物可具有降低之給藥要求(例如,用於達成所要作用之較低劑量數或較低劑型)及/或可產生較低之代謝物負荷。
通式(I)化合物可具有多個潛在的代謝攻擊位點。為最佳化上述關於物理化學特性及代謝型態之作用,可選擇具有特定模式之一或多個氘-氫交換的含氘之通式(I)化合物。特定言之,含氘通式(I)化合物中之一或多個氘原子經連接至碳原子及/或位於通式(I)化合物之彼等位置處,該等位置為針對代謝酶,諸如細胞色素P450
之攻擊位點。
當本文使用複數形式之措詞化合物、鹽、多晶型物、水合物、溶劑合物及其類似物時,此亦理解為意謂單個化合物、鹽、多晶型物、異構體、水合物、溶劑合物或其類似物。
「穩定化合物」或「穩定結構」意謂足夠穩固以經受住自反應混合物分離至適用純度且調配成有效治療劑之化合物。
視各種所需取代基之位置及性質而定,本發明化合物視情況含有一或多個不對稱中心。一或多個不對稱碳原子有可能以(R)或(S)組態存在,此可在單一不對稱中心的情況下產生外消旋混合物且在多個不對稱中心的情況下產生非對映異構混合物。在某些情況下,不對稱性亦有可能由於圍繞給定鍵(例如與指定化合物之兩個經取代芳環鄰接的中心鍵)限制性旋轉而存在。
較佳化合物為產生更需要之生物活性的化合物。本發明化合物之經分離的純或部分純化異構體及立體異構體或外消旋或非對映異構體混合物亦包括在本發明之範疇內。此類物質之純化及分離可藉由此項技術中已知之標準技術實現。
較佳異構體為產生較多所需生物活性之彼等異構體。本發明化合物之此等經分離的、純的或部分純化的異構體或外消旋混合物亦包括在本發明之範疇內。此類物質之純化及分離可藉由此項技術中已知之標準技術實現。
光學異構體可藉由根據習知方法解析外消旋混合物,例如藉由使用光活性酸或鹼形成非對映異構鹽,或形成共價非對映異構體來獲得。適當酸之實例為酒石酸、二乙醯基酒石酸、二甲苯醯基酒石酸及樟腦磺酸。非對映異構體之混合物可藉由此項技術中已知之方法(例如藉由層析或分步結晶)基於其物理及/或化學差異而分離成其個別非對映異構體。隨後自經分離之非對映異構鹽中釋放光學活性鹼或酸。分離光學異構體之不同方法涉及在進行或不進行習知衍生之情況下使用對掌性層析(例如使用對掌相之HPLC管柱),最佳選擇習知衍生以使對映異構體之分離最大化。使用對掌性相之適合HPLC管柱為可商購的,諸如由Daicel製造之管柱,例如Chiracel OD及Chiracel OJ,例如以及許多其他管柱,其均為可常規選擇的。在進行或不進行衍生之情況下的酶分離亦為適用的。本發明之光學活性化合物同樣可藉由利用光學活性起始物質之對掌性合成來獲得。
為了將不同類型之異構體彼此區分開,參考IUPAC規則E部分(Pure Appl Chem 45, 11-30, 1976)。
本發明包括本發明化合物之所有可能立體異構體,其呈單一立體異構體形式或呈該等立體異構體(例如(R)或(S)異構體)之任何比率之任何混合物形式。藉由任何適合之現有技術水平方法(諸如層析法,尤其對掌性層析)來達成本發明化合物之單一立體異構體(例如單一對映異構體或單一非對映異構體)之分離。
本發明包括本發明化合物之全部可能互變異構體,其呈單一互變異構體形式或該等互變異構體的任何比率之任何混合物形式。
此外,本發明化合物可以N-氧化物形式存在,其定義為本發明化合物之至少一個氮經氧化。本發明包括全部此類可能的N-氧化物。
本發明亦涵蓋本發明化合物之有用形式,諸如代謝物、水合物、溶劑合物、前藥、鹽(尤其醫藥學上可接受之鹽)及/或共沈澱物。
本發明化合物可以水合物或溶劑合物形式存在,其中本發明化合物含有極性溶劑(尤其,例如水、甲醇或乙醇)作為化合物之晶格的結構元素。極性溶劑(特定言之水)之量可以化學計量或非化學計量比率存在。在化學計量溶劑合物(例如水合物)之情況下,半(hemi)、(半(semi))、單、倍半、二、三、四、五等溶劑合物或水合物分別為可能的。本發明包括所有此類水合物或溶劑合物。
此外,本發明化合物有可能以游離形式(例如以游離鹼形式、或以游離酸形式、或以兩性離子形式)存在,或以鹽形式存在。該鹽可為慣用於藥劑學中或用於例如分離或純化本發明化合物之任何鹽,有機或無機加成鹽,尤其任何醫藥學上可接受之有機或無機加成鹽。
術語「醫藥學上可接受之鹽」係指本發明化合物之無機或有機酸加成鹽。舉例而言,參見S. M. Berge等人「Pharmaceutical Salts,」 J. Pharm. Sci. 1977, 66, 1-19。
本發明化合物之適合醫藥學上可接受之鹽可為例如在鏈或環中攜帶有氮原子之本發明化合物的酸加成鹽,例如其呈足夠的鹼性,諸如與無機酸或「礦物酸」之酸加成鹽,該無機酸諸如鹽酸、氫溴酸、氫碘酸、硫酸、胺磺酸、重硫酸、磷酸或硝酸,例如或與有機酸之酸加成鹽,該有機酸諸如甲酸、乙酸、乙醯乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水楊酸、2-(4-羥基苯甲醯基)-苯甲酸、樟腦酸、肉桂酸、環戊丙酸、二葡萄糖酸、3-羥基-2-萘甲酸、菸鹼酸、雙羥萘酸、果膠酯酸、3-苯基丙酸、特戊酸、2-羥基乙磺酸、衣康酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、對甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟腦磺酸、檸檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、丁二酸、蘋果酸、己二酸、海藻酸、順丁烯二酸、反丁烯二酸、D-葡萄糖酸、杏仁酸、抗壞血酸、葡糖庚酸、甘油磷酸、天冬胺酸、磺基水楊酸或硫氰酸。
此外,呈足夠酸性之本發明化合物的另一適合醫藥學上可接受之鹽為鹼金屬鹽,例如鈉或鉀鹽;鹼土金屬鹽,例如鈣、鎂或鍶鹽;或鋁或鋅鹽;或衍生自氨或具有1至20個碳原子的有機一級、二級或三級胺之銨鹽,該胺諸如乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己胺、二甲胺基乙醇、二乙胺基乙醇、參(羥甲基)胺基甲烷、普魯卡因(procaine)、二苯甲基胺、N
-甲基嗎啉、精胺酸、離胺酸、1,2-乙二胺、N
-甲基哌啶、N
-甲基-還原葡糖胺、N,N
-二甲基-還原葡糖胺、N
-乙基-還原葡糖胺、1,6-己二胺、葡糖胺、肌胺酸、絲胺醇、2-胺基-1,3-丙二醇、3-胺基-1,2-丙二醇、4-胺基-1,2,3-丁三醇;或具有1至20個碳原子之四級銨離子之鹽,該鹽諸如四甲銨、四乙銨、四(正丙基)銨、四(正丁基)銨、N
-苯甲基-N,N,N
-三甲銨、膽鹼或苯甲烴銨。
熟習此項技術者應進一步瞭解,所主張化合物之酸加成鹽有可能藉由使該等化合物與適當無機酸或有機酸經由多種已知方法中之任一者反應而製備。替代地,本發明之酸性化合物之鹼金屬鹽及鹼土金屬鹽藉由使本發明化合物與適當鹼經由多種已知方法反應而製備。
本發明包括本發明化合物之所有可能鹽,其為單一鹽或該等鹽呈任何比率之任何混合物形式。
在本發明文本中,特定言之在實驗部分中,對於本發明之中間物及實例之合成,當化合物經提及為與對應鹼或酸之鹽形式時,如藉由各別製備及/或純化方法獲得之該鹽形式的精確化學計量組成在大多數情況下為未知的。
除非另外說明,否則關於鹽之化學名稱或結構式之後綴,諸如「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x HCl」、「x CF3
COOH」、「x Na+
」意謂鹽形式,該鹽形式之化學計量未指定。
此類似地適用於已藉由所述製備及/或純化方法以(若定義)化學計量組成未知的溶劑合物(諸如水合物)形式獲得合成中間物或實例化合物或其鹽的情況。
此外,本發明包括本發明化合物之所有可能結晶形式或多晶型物,其為單一多晶型物或超過一種多晶型物呈任何比率的混合物形式。
此外,本發明亦包括本發明化合物之前藥。術語「前藥」在此處指示其自身可具有生物學活性或無活性,但在其體內之滯留時間期間轉化(例如,以代謝方式或以水解方式)成本發明化合物的化合物。
根據第一態樣之第二實施例,本發明涵蓋上文通式(I)化合物,其中:
A 為A1或A2,
o 為0、1、2、3或4,
R 選自由以下組成之群:氫、鹵素、氰基、硝基、-OH、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C3
-C6
環烷基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、-S-C1
-C4
鹵代烷基、-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O、S及N-R9
,其中X及Y中之至少一者為CR7
R8
,或
X、Y 一起形成選自由以下組成之群的環成員:-C(O)-O-、-C(O)-NR9
-、-S(O)-NR9
-、-SO2
-NR9
-及-SO2
-O-,
R1
選自由以下組成之群:氫、氰基、-CHO、-OH、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C3
-C6
環烷基、具有1至5個鹵素原子之C3
-C6
鹵代環烷基、C3
-C4
烯基、C3
-C4
炔基、C1
-C4
烷氧基-C1
-C4
烷基、C3
-C6
環烷基-C1
-C3
烷基、氰基-C1
-C4
烷基、-NH-C1
-C4
烷基、-N(C1
-C4
烷基)2
、NH2
-C1
-C4
烷基-、C1
-C4
烷基-NH-C1
-C4
烷基-、(C1
-C4
烷基)2
N-C1
-C4
烷基-、C1
-C4
烷基-C(O)-、具有1至5個鹵素原子之C1
-C4
鹵代烷基-C(O)-、C1
-C4
烷氧基-C(O)-、苯甲氧基-C(O)-、C1
-C4
烷氧基-C1
-C4
烷基-C(O)-、-SO2
-C1
-C4
烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基;
苯基-C1
-C4
烷基,其視情況經獨立地選自由以下組成之群中的1、2、3、4或5個取代基取代:鹵素、-OH、-NO2
、氰基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、 -S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、具有1至5個鹵素原子之-S-C1
-C4
鹵代烷基、具有1至5個鹵素原子之-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基;
雜環基-C1
-C4
烷基,其中雜環基取代基選自由以下組成之群:4員至10員雜環烷基、5員雜芳基及6員雜芳基,其中之每一者視情況經獨立地選自由以下組成之群中的1、2或3個取代基取代:鹵素、-OH、-NO2
、氰基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、 -S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基、具有1至5個鹵素原子之-S-C1
-C4
鹵代烷基、具有1至5個鹵素原子之-S(O)-C1
-C4
鹵代烷基及具有1至5個鹵素原子之-SO2
-C1
-C4
鹵代烷基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或C1
-C4
烷基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,
R7
選自由以下組成之群:氫、-OH、氟、C1
-C4
烷基及C1
-C4
烷氧基,
R8
選自由以下組成之群:氫、-OH、氟、C1
-C4
烷基及C1
-C4
烷氧基,
或R7
及R8
一起形成側氧基(=O),
R9
選自由以下組成之群:氫、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基及C1
-C4
烷氧基,
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,
R11
選自由以下組成之群:氫、C1
-C4
烷基及C1
-C4
烷氧基,
Q 為2,3,5-三氟苯基,
其中當Y為O、S或N-R9
時,R7
、R8
、R10
及R11
中無一者為-OH或C1
-C4
烷氧基,且
其中當X為O、S或N-R9
時,R7
及R8
中無一者為-OH或C1
-C4
烷氧基;
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第三實施例,本發明涵蓋上文通式(I)化合物,其中:
A 為A1或A2,
o 為0、1或2,
R 選自由以下組成之群:鹵素、C1
-C4
烷基及C1
-C4
烷氧基、氰基、具有1至5個鹵素原子之C1
-C4
鹵烷基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O、S及N-R9
,其中X及Y中之至少一者為CR7
R8
,
R1
選自由以下組成之群:氫、C1
-C4
烷基、C3
-C6
環烷基、C3
-C4
烯基、C3
-C4
炔基、C1
-C4
烷氧基-C1
-C4
烷基、C3
-C6
環烷基-C1
-C3
烷基、氰基-C1
-C4
烷基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或C1
-C4
烷基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,
R11
為氫,
Q 為2,3,5-三氟苯基,
其中當Y為O、S或N-R9
時,R10
不為-OH或C1
-C4
烷氧基;
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第四實施例,本發明涵蓋上文通式(I)化合物,其中:
A 為A1或A2,
o 為0、1或2,
R 選自由以下組成之群:鹵素、C1
-C4
烷基、C1
-C4
烷氧基及氰基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X 選自由以下組成之群:CR7
R8
、O、S及N-R9
,
Y 為CR7
R8
或O,
R1
為氫或C1
-C4
烷基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或C1
-C4
烷基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、-NH2
,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基,
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH及C1
-C4
烷基,
R11
為氫
Q 為2,3,5-三氟苯基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第五實施例,本發明涵蓋上文通式(I)化合物,其中:
A 選自由以下組成之群: ,
R1
為氫或甲基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或甲基,
R4
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基、甲氧基、三氟甲基、三氟甲氧基及NH2
,較佳地氫、氟、氯及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基、甲氧基及三氟甲基,
R6
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基及甲氧基,
Q 為2,3,5-三氟苯基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第六實施例,本發明涵蓋上文通式(I)化合物,其中:
A 選自由以下組成之群: ,
R1
為氫或甲基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或甲基,
R4
選自由以下組成之群:氫、氯、氟、甲基、甲氧基、異丙氧基及三氟甲基,較佳地氫、氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、氯、氟、-OH、氰基、甲基、三氟甲氧基及NH2
,
R6
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基及甲氧基,
Q 為2,3,5-三氟苯基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第七實施例,本發明涵蓋上文通式(I)化合物,其中:
A 選自由以下組成之群: ,
R1
為氫或甲基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或甲基,
R4
選自由以下組成之群:氫、氯、氟、-OH、氰基、甲基、甲氧基、三氟甲基、三氟甲氧基及NH2
,較佳地氫、氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、氯、氟、-OH、氰基、甲基、甲氧基及三氟甲基,
R6
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基及甲氧基,
Q 為2,3,5-三氟苯基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據第一態樣之第八實施例,本發明涵蓋上文通式(I)化合物,其中:
A 為A3或A4
o 為0或1,
R 選自由以下組成之群:鹵素、C1
-C4
烷基、C1
-C4
烷氧基及氰基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X 選自由以下組成之群:CR7
R8
、O、S及N-R9
,
Y 為CR7
R8
或O,
R1
為氫或C1
-C4
烷基,
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
R3
為氫或C1
-C4
烷基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、NH2
,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基,
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH及C1
-C4
烷基,
R11
為氫,
Q 為2,3,5-三氟苯基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
本發明之第一態樣之其他實施例:
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0、1或2,
R 選自由以下組成之群:鹵素、C1
-C4
烷基及C1
-C4
烷氧基、氰基、具有1至5個鹵素原子之C1
-C4
鹵烷基,
Rp
為氫,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O、S及N-R9
,其中X及Y中之至少一者為CR7
R8
,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,及
R11
為氫,
其中當Y為O、S或N-R9
時,R10
不為-OH或C1
-C4
烷氧基,
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0、1或2,
R 選自由以下組成之群:鹵素、C1
-C4
烷基及C1
-C4
烷氧基、氰基、具有1至5個鹵素原子之C1
-C4
鹵烷基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O、S及N-R9
,其中X及Y中之至少一者為CR7
R8
,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,及
R11
為氫,
其中當Y為O、S或N-R9
時,R10
不為-OH或C1
-C4
烷氧基,
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0、1或2,
R 選自由以下組成之群:鹵素、C1
-C4
烷基及C1
-C4
烷氧基、氰基、具有1至5個鹵素原子之C1
-C4
鹵烷基,
Rp
為氫,
X、Y 獨立地選自由以下組成之群:CR7
R8
、O及S,
其中X及Y中之至少一者為CR7
R8
,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R10
選自由以下組成之群:氫、-OH、C1
-C4
烷基及C1
-C4
烷氧基,及
R11
為氫,
其中當Y為O、S或N-R9
時,R10
不為-OH,
且其中不包括根據下式之化合物:
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0或1,
R 選自由以下組成之群:鹵素、C1
-C4
烷基、C1
-C4
烷氧基及氰基,
Rp
為氫,
X 選自由以下組成之群:CR7
R8
、O、S及N-R9
,
Y 為CR7
R8
,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH及C1
-C4
烷基,及
R11
為氫,
且其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0或1,
R 選自由以下組成之群:鹵素、C1
-C4
烷基、C1
-C4
烷氧基及氰基,
Rp
選自由以下組成之群:氫、C1
-C4
烷基,
X 選自由以下組成之群:CR7
R8
、O、S及N-R9
,
Y 為CR7
R8
或O,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R9
為C1
-C4
烷基,
R10
選自由以下組成之群:氫、-OH及C1
-C4
烷基,及
R11
為氫,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A1或A2,
o 為0或1,
R 選自由以下組成之群:鹵素、C1
-C4
烷基、C1
-C4
烷氧基及氰基,
Rp
為氫,
X 選自由以下組成之群:CR7
R8
、O及S,
Y 為CR7
R8
或O,
R7
選自由以下組成之群:氫及C1
-C4
烷基,
R8
選自由以下組成之群:氫及C1
-C4
烷基,
或R7
及R8
一起形成側氧基(=O),
R10
選自由以下組成之群:氫、-OH及C1
-C4
烷基,及
R11
為氫,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 選自由以下組成之群:
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 選自由以下組成之群: ,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 選自由以下組成之群:, ,
較佳地 ,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 選自如上文任何地方所定義之群組A1
;
較佳地,A為;
限制條件為當R2
為乙基時且當A為時R4
不為氫。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R2
選自由以下組成之群:四氫-2H-哌喃-4-基、3,6-二氫-2H-哌喃-4-基、乙基及3-氟氮雜環丁-1-基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
Rp
為氫或C1
-C4
烷基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
Rp
為氫或甲基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R3
為氫或C1
-C4
烷基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R3
為氫或甲基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、NH2
,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R4
選自由以下組成之群:氫、氯、氟、-OH、氰基、甲基、甲氧基、異丙氧基、三氟甲基、三氟甲氧基及NH2
,較佳地氫、氟、氯、甲氧基及異丙氧基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R5
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R5
選自由以下組成之群:氫、氯、氟、-OH、氰基、甲基、甲氧基及三氟甲基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R6
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R6
選自由以下組成之群:氫、氟、氯、-OH、氰基、甲基及甲氧基,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R2
為四氫-2H-哌喃-4-基,
Q 為2,3,5-三氟苯基,
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R2
為3,6-二氫-2H-哌喃-4-基,
Q 為2,3,5-三氟苯基,
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R2
為乙基,
R4
選自由以下組成之群:氫、鹵素、-OH、氰基、C1
-C4
烷基、C3
-C6
環烷基、具有1至5個鹵素原子之C1
-C4
鹵代烷基、C1
-C4
烷氧基-C1
-C4
烷基、C1
-C4
烷氧基、具有1至5個鹵素原子之C1
-C4
鹵代烷氧基、C1
-C4
烷基-C(O)-、-NH2
、-NH(C1
-C4
烷基)、-N(C1
-C4
烷基)2
、-S-C1
-C4
烷基、-S(O)-C1
-C4
烷基、-SO2
-C1
-C4
烷基,較佳地氫、鹵素及C1
-C4
烷氧基,更佳地氟、氯、甲氧基及異丙氧基,
Q 為2,3,5-三氟苯基,
限制條件為當A為時,R4
不為氫;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
R2
為3-氟氮雜環丁-1-基,
Q 為2,3,5-三氟苯基,
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在第一態樣之另一實施例中,本發明涵蓋上文式(I)化合物,其中:
A 為A3或A4
其中
Rp
選自由以下組成之群:氫、C1
-C4
烷基;較佳地氫,
其中不包括根據下式之化合物:;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
在本文中任何位置描述之任一或所有實施例中之本發明之另一態樣中,不包括如上文所定義之X及/或Y「NR9
」之定義。
在另一態樣中,本發明涵蓋如本文中之實施例中之任一者所定義的式(I)化合物,其中:
R4
具有如本文任何地方所定義之含義,限制條件為當R2
為乙基時且當A為時,R4
不為氫。
另外,本發明不包括根據下式之化合物:。
在第一態樣之另一特定實施例中,本發明涵蓋標題「本發明之第一態樣的其他實施例」下之上述實施例中之兩者或更多者的組合。
本發明涵蓋上文通式(I)化合物之本發明之任何實施例或態樣內的任何子組合。
本發明涵蓋下文本文實例部分中所揭示之通式(I)化合物。
本發明之通式(I)化合物可根據如本發明之實驗部分(通用程序)中所示之流程1-5製備。所述之流程及程序說明本發明之通式(I)化合物之合成途徑且不意欲具有限制性。熟習此項技術者顯而易知,可以各種方式修改如流程1-5中所例示之轉化次序。因此,此等流程中所例示之轉化次序不希望具有限制性。另外,可在所例示之轉化之前及/或之後達成取代基Q、A、R1
、R2
、R3
、R4
、R5
或R6
中之任一者之相互轉化。此等修改可為,諸如保護基引入、保護基裂解、官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者所已知之其他反應。此等轉化包括引入允許取代基進一步相互轉化之官能基的轉化。合適保護基及其引入及裂解為熟習此項技術者所熟知的(參見例如T.W. Greene及P.G.M. Wuts in Protective Groups in Organic Synthesis,第3版, Wiley 1999)。特定實例描述於後續段落中。
根據第二態樣,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式1N
之中間化合物:,
其中A、R1
、R3
、R4
、R5
、R6
及Q如關於如上文所定義之通式(I)化合物所定義,且Hal為鹵素,特定言之氯及溴,與通式1F
化合物反應:
R2
H1F
,
其中R2
為3-氟氮雜環丁烷,
由此得到通式(I)化合物:,
其中A、R1
、R3
、R4
、R5
、R6
及Q如上文所定義且R2
為3-氟氮雜環丁烷,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據第二態樣之一替代性實施例,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式1T
之中間化合物:,
其中A、R1
、R2
、R3
、R4
、R5
及R6
如關於如上文所定義之通式(I)化合物所定義,且其中Hal為鹵素,特定言之氯、溴或碘,
限制條件為當R2
為乙基時且當A為時,R4
不為氫;
與通式1H
化合物反應:
Q-B(OR)2 1H
,
其中Q為2,3,5-三氟苯基,且各R可分別為H或Me或兩個R均為頻哪醇酯,
由此得到通式(I)化合物:,
其中A、R1
、R2
、R3
、R4
、R5
及R6
如上文所定義且Q為2,3,5-三氟苯基,
限制條件為當R2
為乙基時且當A為時,R4
不為氫,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據第二態樣之一替代性實施例,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式1W
之中間化合物:,
其中Q、R2
、R3
、R4
、R5
及R6
如關於如上文所定義之通式(I)化合物所定義,
限制條件為當R2
為乙基時且當A為時,R4
不為氫;
與通式1M
化合物反應:,
其中R1
及A如關於如上文所定義之通式(I)化合物所定義,
由此得到通式(I)化合物:,
其中A、R1
、R2
、R3
、R4
、R5
、R6
及Q如上文所定義,
限制條件為當R2
為乙基時且當A為時,R4
不為氫,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據第二態樣之一替代性實施例,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式1N
之中間化合物:,
其中Q、A、R1
、R3
、R4
、R5
及R6
如關於如上文所定義之通式(I)化合物所定義,且Hal為鹵素,特定言之氯及溴,
與通式2A
化合物反應:
R2
Met-X2A
,
其中R2
為乙基或3,6-二氫-2H-哌喃-4-基,Met為鎂或鋅,以及X為氯、溴或碘,
限制條件為當R2
為乙基時且當A為時,R4
不為氫;
由此得到通式(I)化合物:,
其中A、R1
、R3
、R4
、R5
、R6
及Q如上文所定義且R2
為乙基或3,6-二氫-2H-哌喃-4-基,限制條件為當R2
為乙基時且當A為時,R4
不為氫,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據第二態樣之一替代性實施例,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式1N
之中間化合物:,
其中Q、A、R1
、R3
、R4
、R5
及R6
如關於如上文所定義之通式(I)化合物所定義,且Hal為鹵素,特定言之氯及溴,
與通式2P
化合物反應:,
其中R2
為乙基或3,6-二氫-2H-哌喃-4-基,且各R可分別為H或Me或兩個R均為頻哪醇酯,
限制條件為當R2
為乙基時且當A為時,R4
不為氫;
由此得到通式(I)化合物:,
其中A、R1
、R3
、R4
、R5
、R6
及Q如上文所定義且R2
為乙基或3,6-二氫-2H-哌喃-4-基,
限制條件為當R2
為乙基時且當A為時,R4
不為氫,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據第二態樣之一替代性實施例,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式I-b1
之中間化合物:,
其中Q、A、R1
、R3
、R4
、R5
及R6
如關於如上文所定義之通式(I)化合物所定義,
在存在催化劑(類似地鈀/木炭)的情況下與氫(H2
)反應,
由此得到通式(I)化合物:,
其中A、R1
、R3
、R4
、R5
、R6
及Q如上文所定義且R2
為四氫哌喃-4-基,
隨後視情況使用對應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
根據一第三態樣,本發明涵蓋適用於製備上文通式(I)化合物之中間化合物。
特定言之,本發明涵蓋通式(II)之中間化合物:,
其中
R2
為-OH或如關於上文通式(I)化合物所定義,
R3
、R4
、R5
、R6
及Q如關於上文通式(I)化合物所定義,且
RA
為H或C1
-C4
烷基,
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及其混合物。
根據一第四態樣,本發明涵蓋使用該等中間化合物以製備如上文所定義之通式(I)化合物。
特定言之,本發明涵蓋使用通式(II)之中間化合物:,
其中
R2
為-OH或如關於上文通式(I)化合物所定義,
R3
、R4
、R5
、R6
及Q如關於上文通式(I)化合物所定義,且
RA
為H或C1
-C4
烷基,
以製備如上文所定義之通式(I)化合物。
本發明涵蓋下文此文本之實例部分中所揭示之中間化合物。
本發明之通式(I)化合物可藉由熟習此項技術者已知之任何方法轉化為如本文所述之任何鹽,較佳地醫藥學上可接受之鹽。類似地,本發明之通式(I)化合物之任何鹽可藉由熟習此項技術者已知之任何方法轉換為游離化合物。
本發明之通式(I)化合物展現尚不可預測之有價值的藥理學作用範圍。已出人意料地發現,本發明化合物與Slo-1有效地相互作用,且因此,該等化合物有可能用於治療或預防疾病,較佳地人類及動物之蠕蟲感染,特定言之胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染。
本發明化合物可用以控制、治療及/或預防蠕蟲感染,尤其胃腸及腸外蠕蟲感染。此方法包含向有需要之哺乳動物投與一定量之本發明化合物或其醫藥學上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯;其有效治療病症。
在一替代態樣中,此方法包含向有需要之鳥,亦即籠鳥,或特定言之家禽投與一定量之本發明化合物或其醫藥學上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯;其有效治療病症。
特定言之,在獸醫學領域中,本發明化合物適用於在溫血動物中在有利毒性下控制發生在牲畜、育種、動物園、實驗室、實驗用及家畜動物中之動物育種及動物飼養中的寄生蟲,特定言之蠕蟲。其對寄生蟲、特定言之蠕蟲發育之所有或特定階段具有活性。
農業牲畜包括例如哺乳動物,諸如綿羊、山羊、馬、驢、駱駝、水牛、兔、馴鹿、黃鹿,且特定言之牛及豬;或家禽,諸如火雞、鴨、鵝,且特定言之雞;或例如在水產養殖中之魚或甲殼動物。
家畜包括例如哺乳動物,諸如倉鼠、天竺鼠、大鼠、小鼠、南美栗鼠、雪貂或特定言之犬、貓;籠養鳥;爬行動物;兩棲動物或水族箱魚。
本發明亦提供治療蠕蟲感染,特定言之胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染之方法。
此等病症已在動物中充分表徵,且可藉由投與本發明之醫藥組合物來治療。
如本發明文本中所用,術語「治療(treating/treatment)」係習知地使用,例如管理或護理個體以達到對抗、減輕、減少、緩解、改良疾病或病症(諸如線蟲感染)之病況之目的。特定言之,且尤其在動物健康狀況或獸醫學領域中,術語「治療」包括預防性、病後調節性(metaphylactic)或治療性治療。
對人類或動物具有致病性之蠕蟲包括例如棘頭蟲(acanthocephala)、線蟲、舌形蟲(pentastoma)及扁形蟲(platyhelmintha)(例如單殖蟲(monogenea)、絛蟲及吸蟲)。
例示性蠕蟲包括(但不限於):
單殖蟲:例如指環蟲屬(Dactylogyrus spp.)、三代蟲屬(Gyrodactylus spp.)、小盤蟲屬(Microbothrium spp.)、多盤蟲屬(Polystoma spp.)、穴頭蟲屬(Troglocephalus spp.)
絛蟲:來自假葉目(the order of the Pseudophyllidea),例如:溝槽絛蟲屬(Bothridium spp.)、裂頭絛蟲屬(Diphyllobothrium spp.)、複殖孔絛蟲屬(Diplogonoporus spp.)、食魚絛蟲屬(Ichthyobothrium spp.)、舌狀絛蟲屬(Ligula spp.)、頭裂絛蟲屬(Schistocephalus spp.)、迭宮絛蟲屬(Spirometra spp.)
來自圓葉目(the order of the Cyclophyllida),例如:愛達絛蟲屬(Andyra spp.)、裸頭絛蟲屬(Anoplocephala spp.)、無卵黃腺屬(Avitellina spp.)、伯特絛蟲屬(Bertiella spp.)、錫帶絛蟲屬(Cittotaenia spp.)、戴文絛蟲屬(Davainea spp.)、雙睾絛蟲屬(Diorchis spp.)、倍殖孔絛蟲屬(Diplopylidium spp.)、複孔絛蟲屬(Dipylidium spp.)、胞蟲屬(Echinococcus spp.)、棘葉絛蟲屬(Echinocotyle spp.)、棘鱗絛蟲屬(Echinolepis spp.)、泡尾絛蟲屬(Hydatigera spp.)、膜殼絛蟲屬(Hymenolepis spp.)、喬伊絛蟲屬(Joyeuxiella spp.)、中殖孔絛蟲屬(Mesocestoides spp.)、莫尼茨絛蟲屬(Moniezia spp.)、副裸頭絛蟲屬(Paranoplocephala spp.)、瑞列絛蟲屬(Raillietina spp.)、斯泰絛蟲屬(Stilesia spp.)、帶絛蟲屬(Taenia spp.)、曲子宮絛蟲屬(Thysaniezia spp.)、遂體絛蟲屬(Thysanosoma spp),
吸蟲:來自複殖目(the class of the Digenea),例如:澳畢吸蟲屬(Austrobilharzia spp.)、短咽吸蟲屬(Brachylaima spp.)、杯殖吸蟲屬(Calicophoron spp.)、下彎吸蟲屬(Catatropis spp)、分枝睾吸蟲屬(Clonorchis spp.)、肛瘤吸蟲屬(Collyriclum spp.)、殖盤吸蟲屬(Cotylophoron spp.)、環腸吸蟲屬(Cyclocoelum spp.)、雙腔吸蟲屬(Dicrocoelium spp.)、複口吸蟲屬(Diplostomum spp.)、棘隙吸蟲屬(Echinochasmus spp.)、棘緣吸蟲屬(Echinoparyphium spp.)、棘口吸蟲屬(Echinostoma spp.)、闊盤吸蟲(Eurytrema spp.)、片吸蟲屬(Fasciola spp.)、擬片形吸蟲屬(Fasciolides spp.)、薑片吸蟲(Fasciolopsis spp.)、菲策吸蟲屬(Fischoederius spp.)、腹袋吸蟲屬(Gastrothylacus spp.)、巨畢吸蟲屬(Gigantobilharzia spp.)、巨盤吸蟲屬(Gigantocotyle spp.)、異形吸蟲屬(Heterophyes spp.)、低頸吸蟲屬(Hypoderaeum spp.)、彩蚴吸蟲屬(Leucochloridium spp.)、後殖吸蟲屬(Metagonimus spp.)、次睾吸蟲屬(Metorchis spp.)、侏形吸蟲屬(Nanophyetus spp.)、背孔吸蟲屬(Notocotylus spp.)、後睾吸蟲屬(Opisthorchis spp.)、鳥畢吸蟲屬(Ornithobilharzia spp.)、并殖吸蟲屬(Paragonimus spp.)、同盤吸蟲屬(Paramphistomum spp.)、斜睾吸蟲屬(Plagiorchis spp.)、雙穴吸蟲屬(Posthodiplostomum spp.)、前殖吸蟲屬(Prosthogonimus spp.)、裂體吸蟲屬(Schistosoma spp.)、毛畢吸蟲屬(Trichobilharzia spp.)、隱孔吸蟲屬(Troglotrema spp.)、盲腔吸蟲屬(Typhlocoelum spp.)
線蟲:來自毛形線蟲(the order of the Trichinellida)目,例如:毛細線蟲屬(Capillaria spp.)、革自線蟲屬(Eucoleus spp.)、菲律賓毛細線蟲屬(Paracapillaria spp.)、旋毛線蟲屬(Trichinella spp.)、催科線蟲屬(Trichomosoides spp.)、鞭形線蟲屬(Trichuris spp.)、
來自墊刃目(the order of the Tylenchida),例如:微頸線蟲屬(Micronema spp.)、擬類圓線蟲屬(Parastrongyloides spp.)、糞類圓線蟲屬(Strongyloides spp.)
來自小桿亞目(the order of the Rhabditina),例如:貓圓線蟲屬(Aelurostrongylus spp.)、裂口線蟲屬(Amidostomum spp.)、鉤口線蟲屬(Ancylostoma spp.)、血管圓線蟲屬(Angiostrongylus spp.)、羚羊線蟲屬(Bronchonema spp.)、仰口線蟲屬(Bunostomum spp.)、夏柏特線蟲屬(Chabertia spp.)、古柏線蟲屬(Cooperia spp.)、類古柏線蟲屬(Cooperioides spp.)、環體線蟲屬(Crenosoma spp.)、盅口線蟲屬(Cyathostomum spp.)、環尾線蟲屬(Cyclococercus spp.)、環齒口線蟲屬(Cyclodontostomum spp.)、杯環線蟲屬(Cylicocyclus spp.)、杯冠線蟲屬(Cylicostephanus spp.)、柱咽線蟲屬(Cylindropharynx spp.)、囊尾線蟲屬(Cystocaulus spp.)、網尾線蟲屬(Dictyocaulus spp.)、圓線蟲屬(Elaphostrongylus spp.)、類絲線蟲屬(Filaroides spp.)、球首線蟲屬(Globocephalus spp.)、細紋線蟲屬(Graphidium spp.)、輻首線蟲屬(Gyalocephalus spp.)、血矛線蟲屬(Haemonchus spp.)、螺旋線蟲屬(Heligmosomoides spp.)、豬圓線蟲屬(Hyostrongylus spp.)、馬歇爾線蟲屬(Marshallagia spp.)、後圓線蟲屬(Metastrongylus spp.)、繆勒線蟲屬(Muellerius spp.)、鉤口線蟲屬(Necator spp.)、細頸線蟲屬(Nematodirus spp.)、新圓線蟲屬(Neostrongylus spp.)、日圓線蟲屬(Nippostrongylus spp.)、尖柱線蟲屬(Obeliscoides spp.)、食道齒線蟲屬(Oesophagodontus spp.)、結節線蟲屬(Oesophagostomum spp.)、盤頭線蟲屬(Ollulanus spp.)、鳥圓線蟲屬(Ornithostrongylus spp.)、奧斯勒線蟲屬(Oslerus spp.)、奧斯特線蟲屬(Ostertagia spp.)、副古柏線蟲屬(Paracooperia spp.)、擬環體線蟲屬(Paracrenosoma spp.)、擬類線蟲屬(Parafilaroides spp.)、擬馬鹿圓線蟲屬(Parelaphostrongylus spp.)、肺尾線蟲屬(Pneumocaulus spp.)、肺圓線蟲屬(Pneumostrongylus spp.)、盂口線蟲屬(Poteriostomum spp.)、原圓線蟲屬(Protostrongylus spp.)、銳尾線蟲屬(Spicocaulus spp.)、冠線蟲屬(Stephanurus spp.)、圓形線蟲屬(Strongylus spp.)、比翼線蟲屬(Syngamus spp.)、背帶線蟲屬(Teladorsagia spp.)、毛線線蟲屬(Trichonema spp.)、毛圓線蟲屬(Trichostrongylus spp.)、三齒線蟲屬(Triodontophorus spp.)、隱圓線蟲屬(Troglostrongylus spp.)、鉤刺線蟲屬(Uncinaria spp.)
來自旋尾目(the order of the Spirurida),例如:棘唇線蟲屬(Acanthocheilonema spp.)、異尖線蟲屬(Anisakis spp.)、蛔形線蟲屬(Ascaridia spp.);蛔線蟲屬(Ascaris spp.)、似蛔線蟲屬(Ascarops spp.)、無刺線蟲屬(Aspiculuris spp.)、貝蛔線蟲屬(Baylisascaris spp.)、布魯線蟲屬(Brugia spp.)、瑟科線蟲屬(Cercopithifilaria spp.)、旋尾線蟲屬(Crassicauda spp.)、棘唇線蟲屬(Dipetalonema spp.)、惡線蟲屬(Dirofilaria spp.)、龍線蟲屬(Dracunculus spp.);德拉西線蟲屬(Draschia spp.)、住腸線蟲屬(Enterobius spp.)、絲蟲屬(Filaria spp.)、顎口線蟲屬(Gnathostoma spp.)、筒線蟲屬(Gongylonema spp.)、柔線蟲屬(Habronema spp.)、異刺線蟲屬(Heterakis spp.);光絲蟲屬(Litomosoides spp.)、羅阿線蟲屬(Loa spp.)、蟠尾絲蟲屬(Onchocerca spp.)、蟯蟲屬(Oxyuris spp.)、副柔線蟲屬(Parabronema spp.)、類絲蟲屬(Parafilaria spp.)、副蛔蟲屬(Parascaris spp.)、栓尾線蟲屬(Passalurus spp.)、泡翼線蟲屬(Physaloptera spp.)、普氏線蟲屬(Probstmayria spp.)、偽絲蟲屬(Pseudofilaria spp.)、絲狀線蟲屬(Setaria spp.)、思科線蟲屬(Skjrabinema spp.)、旋尾線蟲屬(Spirocerca spp.)、冠絲蟲屬(Stephanofilaria spp.)、多圓線蟲屬(Strongyluris spp.)、管狀線蟲屬(Syphacia spp.)、吸吮線蟲屬(Thelazia spp.)、弓蛔線蟲屬(Toxascaris spp.)、弓首線蟲屬(Toxocara spp.)、吳策線蟲屬(Wuchereria spp.)
棘頭動物(Acantocephala):來自寡棘吻目(the order of the Oligacanthorhynchida),例如:巨吻棘蟲屬(Macracanthorhynchus spp.)、棘頭蟲前睾屬(Prosthenorchis spp.);來自鏈珠目(the order of the Moniliformida),例如:念珠棘蟲屬(Moniliformis spp.)
來自多形目(the order of the Polymorphida),例如:細頸棘頭蟲屬(Filicollis spp.);來自棘吻目(the order of the Echinorhynchida),例如:棘頭蟲屬(Acanthocephalus spp.)、棘吻蟲屬(Echinorhynchus spp.)、似細吻棘頭蟲屬(Leptorhynchoides spp.)
螠蟲動物(Pentastoma):來自孔頭舌蟲目(the order of the Porocephalida),例如:舌形蟲屬(Linguatula spp.)
本發明化合物可尤其用於治療及預防,亦即防治蠕蟲感染,特定言之胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染。
藉由使用本發明化合物控制動物寄生蟲,尤其蠕蟲,希望減少或預防疾病、死亡案例及效能降低(就肉、奶、羊毛、獸皮、蛋、蜂蜜及其類似物而言),以使得能夠更經濟且較簡單飼養動物,且達到動物之良好狀態。
如本文關於動物健康領域所用之術語「控制(control/controlling)」意謂本發明化合物使感染此類寄生蟲之動物中各別寄生蟲之發病率有效降低至無害水準。更特定言之,如本文所用之「控制」意謂本發明化合物有效殺死各別寄生蟲,抑制其生長或抑制其增殖。
根據另一態樣,本發明涵蓋如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物,其用於治療或預防疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染。
本發明化合物之醫藥活性可藉由其與Slo-1離子通道之相互作用來加以解釋。
根據另一態樣,本發明涵蓋如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物之用途,其用於治療或預防疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染。
根據另一態樣,本發明涵蓋如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物之用途,其用於治療或預防疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染之方法中。
根據另一態樣,本發明涵蓋如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物之用途,其用於製備用以預防或治療疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染之醫藥組合物,較佳地藥物。
根據另一態樣,本發明涵蓋一種使用有效量之如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物來治療或預防疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染之方法。
根據另一態樣,本發明涵蓋用作抗內寄生蟲劑的如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物。
根據另一態樣,本發明涵蓋用作驅蠕蟲劑,尤其用作殺線蟲劑、殺扁形動物劑(platyhelminthicidal agent)、殺棘頭蟲劑(acanthocephalicidal agent)或殺舌形蟲劑(pentastomicidal agent)的如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物。
根據另一態樣,本發明涵蓋包含如上文所描述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物、鹽,特定言之醫藥學上可接受之鹽或其混合物,及一或多種賦形劑,特定言之一或多種醫藥學上可接受之賦形劑的醫藥組合物,尤其獸醫學調配物。可使用將該等醫藥組合物製備成適當劑型之習知程序。
根據另一態樣,本發明涵蓋一種製備醫藥組合物,特定言之獸醫學調配物之方法,該方法包含以下步驟:將如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物、鹽,特定言之醫藥學上可接受之鹽或其混合物與一或多種賦形劑,特定言之一或多種醫藥學上可接受之賦形劑混合。
根據另一態樣,本發明涵蓋一種使用包含有效量之如上文所述之通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特定言之其醫藥學上可接受之鹽或其混合物之醫藥組合物,特定言之獸醫學調配物來治療或預防疾病,特定言之蠕蟲感染,特別係胃腸及腸外蠕蟲感染,更特定言之胃腸及腸外線蟲感染之方法。
本發明進一步涵蓋包含至少一種本發明化合物,習知地連同一或多種醫藥學上適合之賦形劑地醫藥組合物,特定言之獸醫學調配物,及其用於上文所提及目的之用途。
本發明化合物可具有全身性及/或局部活性。出於此目的,其可以適合之方式進行投與,諸如經由口服、非經腸、經肺、經鼻、舌下、經舌、經頰、經直腸、經陰道、經皮、透皮、經結膜、經耳途徑或以植入物或血管支架形式。此類投與可以預防性、補救性預防或治療性方式進行。
就此等投與途徑而言,本發明化合物有可能以適合之投與形式投與。
就經口投與而言,有可能將本發明化合物調配為此項技術中已知的快速及/或以經修改之方式遞送本發明化合物之劑型,諸如錠劑(非包衣或包衣錠劑,例如具有延遲溶解或不可溶之腸溶或控制釋放包衣)、經口崩解錠劑、薄膜/粉片、薄膜/凍乾製劑、膠囊(例如硬或軟明膠膠囊)、糖包衣錠劑、顆粒劑、丸劑、咀嚼錠(例如軟咀嚼錠)、散劑、乳液、懸浮液、氣霧劑或溶液。有可能將本發明化合物以結晶及/或非晶形及/或溶解形式併入該等劑型中。
非經腸投與可在避免吸收步驟之情況下(例如靜脈內、動脈內、心內、脊椎內或腰內)或在包括吸收之情況下(例如肌肉內、皮下、皮內、經皮或腹膜內)實現。適合於非經腸投與之投與形式尤其為供注射及輸注用之製劑,其呈溶液、懸浮液、乳液、凍乾製劑或無菌粉劑形式。
適用於其他投與途徑之實例為用於吸入之醫藥形式[尤其粉末吸入劑、噴霧器]、經鼻滴劑、經鼻溶液、經鼻噴霧劑;用於經舌、舌下或經頰投與之錠劑/薄膜/粉片/膠囊;栓劑;滴眼劑、眼膏、洗眼液、眼部插入物、滴耳劑、噴耳劑、耳用粉劑、沖耳劑、耳塞;陰道膠囊、水性懸浮液(洗劑、震盪混合物)、親脂性懸浮液、乳液、軟膏、乳膏、經皮治療系統(諸如貼片)、牛奶、糊劑、泡沫、噴滴劑(spot-ons)、敷粉、植入物或血管支架。
本發明化合物可併入所述之投與形式中。此可以本身已知之方式藉由與醫藥學上適合之賦形劑混合而實現。醫藥學上適合之賦形劑尤其包括
● 填充劑及載劑(例如纖維素、微晶纖維素(諸如Avicel®
)、乳糖、甘露糖醇、澱粉、磷酸鈣(諸如Di-Cafos®
)),
● 軟膏基質(例如石油膏、石蠟、甘油三酯、蠟、羊毛蠟、羊毛蠟醇、羊毛脂、親水性軟膏、聚乙二醇),
● 栓劑用基質(例如聚乙二醇、可可黃油、硬脂肪),
● 溶劑(例如水、乙醇、異丙醇、丙三醇、丙二醇、中鏈長甘油三酯脂肪油、液體聚乙二醇、石蠟),
● 界面活性劑、乳化劑、分散劑或潤濕劑(例如十二烷基硫酸鈉)、卵磷脂、磷脂、脂肪醇(諸如Lanette®
)、脫水山梨糖醇脂肪酸酯(諸如Span®)、聚氧乙烯脫水山梨糖醇脂肪酸酯(諸如Tween®)、聚氧乙烯脂肪酸甘油酯(諸如Cremophor®)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(poloxamers)(諸如Pluronic®
),
● 緩衝劑、酸及鹼(例如磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉溶液、碳酸銨、胺丁三醇、三乙醇胺),
● 等滲劑(例如葡萄糖、氯化鈉),
● 吸附劑(例如高分散二氧化矽),
● 增黏劑、凝膠形成劑、增稠劑及/或黏合劑(例如聚乙烯吡咯啶酮、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、羧甲基纖維素鈉、澱粉、卡波姆(carbomers)、聚丙烯酸(諸如Carbopol®
)、海藻酸鹽、明膠),
● 崩解劑(例如經改質澱粉、羧甲基纖維素鈉、羥基乙酸澱粉鈉(諸如Explotab®)、交聯聚乙烯吡咯啶酮、交聯羧甲纖維素鈉(諸如AcDiSol®)),
● 流量調節劑、潤滑劑、滑動劑及脫模劑(例如硬脂酸鎂、硬脂酸、滑石、高分散二氧化矽(諸如Aerosil®)),
● 包衣材料(例如糖、蟲膠)及快速或以修改方式溶解之用於薄膜或擴散膜之成膜劑(例如聚乙烯吡咯啶酮(諸如Kollidon®
)、聚乙烯醇、羥丙基甲基纖維素、羥丙基纖維素、乙基纖維素、鄰苯二甲酸羥丙基甲基纖維素、乙酸纖維素、鄰苯二甲酸乙酸纖維素、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®
)),
● 膠囊材料(例如明膠、羥丙基甲基纖維素),
● 合成聚合物(例如聚乳酸交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®)、聚乙烯吡咯啶酮(諸如Kollidon®)、聚乙烯醇、聚乙酸乙烯酯、聚氧乙烯、聚乙二醇及其共聚物及嵌段共聚物),
● 塑化劑(例如聚乙二醇、丙二醇、丙三醇、三醋酸甘油酯、檸檬酸三乙醯酯、鄰苯二甲酸二丁酯),
● 滲透增強劑,
● 穩定劑(例如抗氧化劑,諸如抗壞血酸、抗壞血酸棕櫚酸酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙酯(propyl gallate)),
● 防腐劑(例如對羥苯甲酸酯、山梨酸、硫柳汞、苯紮氯銨(benzalkonium chloride)、氯己定乙酸酯(chlorhexidine acetate)、苯甲酸鈉),
● 著色劑(例如無機顏料,諸如氧化鐵、二氧化鈦),
● 調味劑、甜味劑、風味劑及/或氣味遮蔽劑。
本發明進一步係關於一種包含至少一種本發明化合物,習知地連同一或多種醫藥學上適合之賦形劑的醫藥組合物,且係關於其根據本發明的用途。
根據另一態樣,本發明涵蓋尤其用於治療及/或預防內及/或外寄生蟲感染之包含至少一種本發明之通式(I)化合物及至少一或多種其他活性成分的醫藥組合,特定言之藥物。
在本發明中,術語「內寄生蟲」如熟習此項技術者所知加以使用,且尤其係指蠕蟲。在本發明中,術語「外寄生蟲」如熟習此項技術者所知加以使用,且尤其係指節肢動物,特定言之昆蟲或蟎。
特定言之,本發明涵蓋醫藥組合,特定言之獸醫學組合,其包含:
● 一或多種第一活性成分,特定言之如上文所定義之通式(I)化合物,及
● 一或多種其他活性成分,特定言之一或多種殺內寄生蟲藥及/或殺外寄生蟲藥。
本發明中之術語「組合」如熟習此項技術者所知加以使用,該組合可能為固定組合、非固定組合或分裝部分之套組。
在本發明中,「固定組合」如熟習此項技術者所知加以使用,且定義為其中例如第一活性成分(諸如一或多種本發明之通式(I)化合物)及另一活性成分一起存在於一個單位劑量或一個單一實體中之組合。「固定組合」之一個實例為醫藥組合物,其中第一活性成分與另一種活性成分存在於供同時投與用的混合物中,諸如調配物中。「固定組合」之另一實例為醫藥組合,其中第一活性成分與另一活性成分存在於一個單位中而未混合。
本發明中之非固定組合或「分裝部分之套組」如熟習此項技術者所知加以使用,且定義為其中第一活性成分與另一活性成分存在於多於一個單位中之組合。非固定組合或分裝部分之套組的一個實例為其中第一活性成分及另一活性成分單獨存在的組合。非固定組合或分裝部分之套組之組分有可能單獨地、依序地、同時地、並行地或按時間順序錯開投與。
本發明化合物可以單一醫藥劑之形式或與一或多種其他醫藥學上活性之成分組合投與,其中該組合不會引起不可接受之不良作用。本發明亦涵蓋此類醫藥組合。舉例而言,本發明化合物可與已知殺外寄生蟲藥及/或殺內寄生蟲藥組合。
本文中藉由其通用名稱指定之其他或另外活性成分已為吾人所知且描述於例如Pesticide Manual (「The Pesticide Manual」,第16版, British Crop Protection Council 2012)中,或可在網際網路(例如http://www.alanwood.net/pesticides)中搜索到。分類係基於本專利申請案申請時之當前IRAC作用模式分類法方案。
殺外寄生蟲藥及/或殺內寄生蟲藥之實例為殺蟲劑、殺蟎劑及殺線蟲劑,且特定言之包括:
(1)乙醯膽鹼酯酶(AChE)抑制劑,諸如胺基甲酸酯類,例如棉靈威(alanycarb)、得滅克(aldicarb)、惡蟲威(bendiocarb)、免扶克(benfuracarb)、丁酮威(butocarboxim)、丁酮碸威(butoxycarboxim)、加保利(carbaryl)、加保扶(carbofuran)、丁基加保扶(carbosulfan)、殺蟲丹(ethiofencarb)、仲丁威(fenobucarb)、複滅蟎(formetanate)、呋線威(furathiocarb)、葉蟬散(isoprocarb)、滅賜克(methiocarb)、納乃得(methomyl)、速滅威(metolcarb)、歐殺滅(oxamyl)、比加普(pirimicarb)、安丹(propoxur)、硫敵克(thiodicarb)、久效威(thiofanox)、唑蚜威(triazamate)、混滅威(trimethacarb)、XMC及滅殺威(xylylcarb);或有機磷酸酯,例如歐殺松(acephate)、亞滅松(azamethiphos)、乙基谷速松(azinphos-ethyl)、甲基谷速松(azinphos-methyl)、硫線磷(cadusafos)、氯氧磷(chlorethoxyfos)、克芬松(chlorfenvinphos)、氯甲磷(chlormephos)、甲基陶斯松(chlorpyrifos-methyl)、蠅毒磷(coumaphos)、殺螟腈(cyanophos)、甲基硫代內吸磷(demeton-S-methyl)、大利松(diazinon)、二氯松(dichlorvos)/DDVP、雙特松(dicrotophos)、大滅松(dimethoate)、甲基毒蟲畏(dimethylvinphos)、二硫松(disulfoton)、EPN、愛殺松(ethion)、普伏松(ethoprophos)、伐滅磷(famphur)、芬滅松(fenamiphos)、撲滅松(fenitrothion)、芬殺松(fenthion)、噻唑磷(fosthiazate)、庚烯磷(heptenophos)、新煙磷(imicyafos)、異柳磷(isofenphos)、O-(甲氧基胺基硫基-磷醯基)水楊酸異丙酯、加福松(isoxathion)、馬拉硫磷(malathion)、滅蚜磷(mecarbam)、達馬松(methamidophos)、滅大松(methidathion)、美文松(mevinphos)、亞素靈(monocrotophos)、二溴磷(naled)、氧樂果(omethoate)、甲基滅多松(oxydemeton-methyl)、甲基巴拉松(parathion-methyl)、賽達松(phenthoate)、福瑞松(phorate)、裕必松(phosalone)、益滅松(phosmet)、福賜米松(phosphamidon)、巴賽松(phoxim)、甲基亞特松(pirimiphos-methyl)、布飛松(profenofos)、巴胺磷(propetamphos)、普硫松(prothiofos)、吡唑硫磷(pyraclofos)、噠嗪硫磷(pyridaphenthion)、喹惡磷(quinalphos)、治螟磷(sulfotep)、丁基嘧啶磷(tebupirimfos)、雙硫磷(temephos)、託福松(terbufos)、樂本松(tetrachlorvinphos)、甲基乙拌磷(thiometon)、三落松(triazophos)、三氯松(triclorfon)及蚜滅多(vamidothion)。
(2) GABA閘控氯通道阻斷劑,諸如環戊二烯-有機氯類,例如氯丹(chlordane)及安殺番(endosulfan)或苯基吡唑(非潑羅(fiproles)),例如乙蟲清(ethiprole)及費普尼(fipronil)。
(3)鈉通道調節劑,諸如擬除蟲菊酯類(pyrethroids),例如阿納寧(acrinathrin)、丙烯除蟲菊酯(allethrin)、d-順式反式丙烯除蟲菊酯、d-反式丙烯除蟲菊酯、畢芬寧(bifenthrin)、生物丙烯除蟲菊、S-環戊烯基生物丙烯除蟲菊異構體、苄呋菊脂(bioresmethrin)、乙氰菊脂(cycloprothrin)、賽扶寧(cyfluthrin)、β-賽扶寧、賽洛寧(cyhalothrin)、λ-賽洛寧、γ-賽洛寧、賽滅寧(cypermethrin)、α-賽滅寧、β-賽滅寧、θ-賽滅寧、ξ-賽滅寧、賽酚寧[(1R)-反式異構體]、第滅寧(deltamethrin)、烯炔菊酯[(EZ)-(1R)-異構體]、益化利(esfenvalerate)、依芬寧(etofenprox)、芬普寧(fenpropathrin)、芬化利(fenvalerate)、護賽寧(flucythrinate)、氟氯苯菊酯(flumethrin)、τ-福化利(tau-fluvalinate)、苄蟎醚(halfenprox)、依普寧(imiprothrin)、噻嗯菊酯(kadethrin)、甲氧苄氟菊酯(momfluorothrin)、百滅寧(permethrin)、苯醚菊酯[(1R)-反式異構體]、普亞列寧(prallethrin)、除蟲菊精(pyrethrins) (除蟲菊(pyrethrum))、苄呋菊脂(resmethrin)、矽護芬(silafluofen)、七氟菊酯(tefluthrin)、治滅寧(tetramethrin)、治滅寧[(1R)-異構體]、泰滅寧(tralomethrin)及拜富寧(transfluthrin)或DDT或甲氧滴滴涕(methoxychlor)。
(4)菸鹼乙醯膽鹼受體(nAChR)競爭性調節劑,諸如新菸鹼類似物類,例如啶蟲脒(acetamiprid)、可尼丁(clothianidin)、呋蟲胺(dinotefuran)、吡蟲啉(imidacloprid)、烯啶蟲胺(nitenpyram)、噻蟲啉(thiacloprid)及噻蟲嗪(thiamethoxam)或菸鹼或氟啶蟲胺腈(sulfoxaflor)或氟吡呋喃酮(flupyradifurone)。
(5)菸鹼乙醯膽鹼受體(nAChR)異位調節劑,諸如賜諾殺類(spinosyn),例如斯平托蘭(spinetoram)及賜諾殺(spinosad)。
(6)麩胺酸閘控氯離子通道(GluCl)異位調節劑,諸如阿維菌素類(avermectin)/米爾倍黴素類(milbemycin),例如阿巴汀(abamectin)、因滅汀苯甲酸酯(emamectin benzoate)、林皮沒丁(lepimectin)及密滅汀(milbemectin)。
(7)青少年激素模擬物,諸如青少年激素類似物,例如烯蟲乙酯(hydroprene)、烯蟲炔酯(kinoprene)及美賜平(methoprene)或芬諾克(fenoxycarb)或百利普芬(pyriproxyfen)。
(9)弦音器官(Chordotonal Organs)之調節劑,諸如派滅淨(pymetrozine)或氟啶蟲醯胺(flonicamid)。
(10)蟎生長抑制劑,諸如克芬蟎(clofentezine)、合賽多(hexythiazox)及氟蟎嗪(diflovidazin)或依殺蟎(etoxazole)。
(12)粒線體ATP合成酶之抑制劑,諸如ATP瓦解劑,諸如汰芬諾克(diafenthiuron)或有機錫化合物,例如三唑錫(azocyclotin)、錫蟎丹(cyhexatin)及芬布錫(fenbutatin oxide)或毆蟎多(propargite)或四氯殺蟎碸(tetradifon)。
(13)經由破壞質子梯度氧化磷酸化之去偶合劑,諸如克凡派(chlorfenapyr)、DNOC及氟蟲胺(sulfluramid)。
(14)菸鹼乙醯膽鹼受體通道阻斷劑,諸如殺蟲磺(bensultap)、培丹鹽酸鹽(cartap hydrochloride)、硫賜安(thiocylam)及殺蟲雙鈉(thiosultap-sodium)。
(15)甲殼素生物合成之抑制劑,0型,諸如雙三氟蟲脲(bistrifluron)、克福隆(chlorfluazuron)、二福隆(diflubenzuron)、氟環脲(flucycloxuron)、氟芬隆(flufenoxuron)、六伏隆(hexaflumuron)、祿芬隆(lufenuron)、諾伐隆(novaluron)、多氟脲(noviflumuron)、得福隆(teflubenzuron)及三福隆(triflumuron)。
(16)甲殼素生物合成之抑制劑,1型,例如布芬淨(buprofezin)。
(17)脫皮干擾劑(特定言之用於雙翅目,亦即雙翅目昆蟲),諸如賽滅淨(cyromazine)。
(18)蛻皮激素受體促效劑,諸如環蟲醯肼(chromafenozide)、合芬隆(halofenozide)、滅芬諾(methoxyfenozide)及得芬諾(tebufenozide)。
(19)章魚胺受體促效劑,諸如三亞蟎(amitraz)。
(20)粒線體複合物III電子傳輸抑制劑,諸如伏蟻腙(hydramethylnone)或亞醌蟎(acequinocyl)或嘧蟎酯(fluacrypyrim)。
(21)粒線體複合物I電子傳輸抑制劑,諸如來自METI殺蟎劑之群,例如芬殺蟎(fenazaquin)、芬普蟎(fenpyroximate)、嘧蟎醚(pyrimidifen)、比達本(pyridaben)、得芬瑞(tebufenpyrad)及脫芬瑞(tolfenpyrad)或魚藤酮(rotenone)(Derris)。
(22)電壓依賴性鈉通道阻斷劑,諸如因得克(indoxacarb)或氰氟蟲胺(metaflumizone)。
(23)乙醯CoA羧化酶之抑制劑,諸如特窗酸(tetronic acid)及特特拉姆酸(tetramic acid)衍生物,例如賜派芬(spirodiclofen)、螺甲蟎酯(spiromesifen)及螺蟲乙酯(spirotetramat)。
(25)粒線體複合物II電子傳輸抑制劑,諸如β-開托利(beta-ketonitrile)衍生物,例如腈吡蟎酯(cyenopyrafen)及丁氟蟎酯(cyflumetofen),及甲苯胺類,諸如吡氟蟎酯(pyflubumide)。
(28)理阿諾鹼(Ryanodine)受體調節劑,諸如二醯胺類,例如氯蟲苯甲醯胺(chlorantraniliprole)、氰強尼普羅(cyantraniliprole)及氟蟲雙醯胺(flubendiamide),
其他活性成分,諸如雙丙環蟲酯(Afidopyropen)、阿福拉納(Afoxolaner)、印楝素(Azadirachtin)、苯氯噻(Benclothiaz)、苯蟎特(Benzoximate)、畢芬載(Bifenazate)、溴蟲氟苯雙醯胺(Broflanilide)、溴蟎酯(Bromopropylate)、蟎離丹(Chinomethionat)、右旋反式氯丙炔菊酯(Chloroprallethrin)、冰晶石(Cryolite)、右旋反式氯丙炔菊酯(Cyclaniliprole)、環氧蟲啶(Cycloxaprid)、氯氟氰蟲醯胺(Cyhalodiamide)、二氯加士(Dicloromezotiaz)、開樂散(Dicofol)、ε-甲氧苄氟菊酯(epsilon-Metofluthrin)、ε-單氟菊酯(epsilon-Momfluthrin)、孚蟎喹(Flometoquin)、三氟咪啶醯胺(Fluazaindolizine)、氟噻蟲碸(Fluensulfone)、氟芬內林(Flufenerim)、氟菌蟎酯(Flufenoxystrobin)、丁蟲腈(Flufiprole)、福薩豐(Fluhexafon)、氟吡菌醯胺(Fluopyram)、弗拉拉納(Fluralaner)、氣釀醯胺(Fluxametamide)、呋喃蟲醯肼(Fufenozide)、戊吡蟲胍(Guadipyr)、右旋七氟甲醚菊酯(Heptafluthrin)、氯噻啉(Imidaclothiz)、依普同(Iprodione)、κ-畢芬寧(kappa-Bifenthrin)、κ-七氟菊酯(kappa-Tefluthrin)、洛替拉納(Lotilaner)、氯氟醚菊酯(Meperfluthrin)、哌蟲啶(Paichongding)、啶蟲丙醚(Pyridalyl)、哌氟喹腙(Pyrifluquinazon)、嘧蟎胺(Pyriminostrobin)、螺蝴雙醋(Spirobudiclofen)、四氟醚菊酯(Tetramethylfluthrin)、氟氰蟲醯胺(Tetraniliprole)、四氯蟲醯胺(Tetrachlorantraniliprole)、硫噁唑芬(Tioxazafen)、硫氟肟醚(Thiofluoximate)、三氟苯嘧啶(Triflumezopyrim)及碘甲烷(iodomethane);另外基於強固芽胞桿菌(Bacillus firmus)之製劑(I-1582, BioNeem, Votivo),以及以下化合物:1-{2-氟-4-甲基-5-[(2,2,2-三氟乙基)亞磺醯基]苯基}-3-(三氟甲基)-1H-1,2,4-三唑-5-胺(自WO2006/043635得知) (CAS 885026-50-6)、{1'-[(2E)-3-(4-氯苯基)丙-2-烯-1-基]-5-氟螺[吲哚-3,4'-哌啶]-1(2H)-基}(2-氯吡啶-4-基)甲酮(自WO2003/106457得知) (CAS 637360-23-7)、2-氯-N-[2-{1-[(2E)-3-(4-氯苯基)丙-2-烯-1-基]哌啶-4-基}-4-(三氟甲基)苯基]異菸鹼醯胺(自WO2006/003494得知) (CAS 872999-66-1)、3-(4-氯-2,6-二甲基苯基)-4-羥基-8-甲氧基-1,8-二氮螺[4.5]癸-3-烯-2-酮(自WO 2010052161得知) (CAS 1225292-17-0)、碳酸3-(4-氯-2,6-二甲基苯基) -8-甲氧基-2-側氧基-1,8-二氮螺[4.5]癸-3-烯-4-基酯乙酯(自EP2647626得知) (CAS 1440516-42-6)、4-(丁-2-炔-1-基氧基)-6-(3,5-二甲基哌啶-1-基)-5-氟嘧啶(自WO2004/099160得知) (CAS 792914-58-0)、 PF1364 (自JP2010/018586得知) (CAS 1204776-60-2)、N-[(2E)-1-[(6-氯吡啶-3-基)甲基]吡啶-2(1H)-亞基]-2,2,2-三氟乙醯胺(自WO2012/029672得知) (CAS 1363400-41-2)、(3E
)-3-[1-[(6-氯-3-吡啶基)甲基-2-伸吡啶基]-1,1,1-三氟-丙-2-酮(自WO2013/144213得知) (CAS 1461743-15-6)、N
-[3-(苯甲基胺甲醯基)-4-氯苯基]-1-甲基-3-(五氟乙基)-4-(三氟甲基)-1H
-吡唑-5-甲醯胺(自WO2010/051926得知) (CAS 1226889-14-0)、5-溴-4-氯-N
-[4-氯-2-甲基-6-(甲基胺甲醯基)苯基]-2-(3-氯-2-吡啶基)吡唑-3-甲醯胺(自CN103232431得知) (CAS 1449220-44-3)、4-[5-(3,5-二氯苯基)-4,5-二氫-5-(三氟甲基)-3-異噁唑基]-2-甲基-N
-(順-1-氧離子基-3-硫雜環丁基)-苯甲醯胺、4-[5-(3,5-二氯苯基)-4,5-二氫-5-(三氟甲基)-3-異噁唑基]-2-甲基-N
-(反-1-氧離子基-3-硫雜環丁基)-苯甲醯胺及4-[(5S
)-5-(3,5-二氯苯基) -4,5-二氫-5-(三氟甲基)-3-異噁唑基]-2-甲基-N
-(順-1-氧離子基-3-硫雜環丁基)苯甲醯胺(自WO 2013/050317 A1得知) (CAS 1332628-83-7)、N
-[3-氯-1-(3-吡啶基)-1H
-吡唑-4-基]-N
-乙基-3-[(3,3,3-三氟丙基)亞磺醯基]-丙醯胺、(+)-N
-[3-氯-1-(3-吡啶基)-1H
-吡唑-4-基]-N
-乙基-3-[(3,3,3-三氟丙基)亞磺醯基]-丙醯胺及(-)-N
-[3-氯-1-(3-吡啶基)-1H
-吡唑-4-基]-N
-乙基 -3-[(3,3,3-三氟丙基)亞磺醯基]-丙醯胺(自WO 2013/162715 A2、WO 2013/162716 A2、US 2014/0213448 A1得知) (CAS 1477923-37-7)、5-[[(2E
)-3-氯-2-丙烯-1-基]胺基]-1-[2,6-二氯-4-(三氟甲基)苯基]-4-[(三氟甲基)亞磺醯基]-1H
-吡唑-3-甲腈(自CN 101337937 A已知) (CAS 1105672-77-2)、3-溴-N
-[4-氯-2-甲基-6-[(甲胺基)硫氧甲基]苯基]-1-(3-氯-2-吡啶基)-1H
-吡唑-5-甲醯胺(Liudaibenjiaxuanan, 自CN 103109816 A得知) (CAS 1232543-85-9);N
-[4-氯-2-[[(1,1-二甲基乙基)胺基]羰基]-6-甲基苯基]-1-(3-氯-2-吡啶基)-3-(氟甲氧基)-1H
-吡唑-5-甲醯胺(自WO 2012/034403 A1得知) (CAS 1268277-22-0)、N
-[2-(5-胺基-1,3,4-噻二唑 -2-基)-4-氯-6-甲基苯基]-3-溴-1-(3-氯-2-吡啶基)-1H
-吡唑-5-甲醯胺(自WO 2011/085575 A1得知) (CAS 1233882-22-8)、4-[3-[2,6-二氯-4-[(3,3-二氯-2-丙烯-1-基)氧基]苯氧基]丙氧基]-2-甲氧基-6-(三氟甲基)-嘧啶(自CN 101337940 A得知) (CAS 1108184-52-6);(2E
)-及2(Z
)-2-[2-(4-氰基苯基)-1-[3-(三氟甲基)苯基]亞乙基]-N
-[4-(二氟甲氧基)苯基]-肼甲醯胺(自CN 101715774 A得知) (CAS 1232543-85-9);3-(2,2-二氯乙烯基)-2,2-二甲基-4-(1H
-苯并咪唑-2-基)苯基-環丙烷甲酸酯(自CN 103524422 A得知) (CAS 1542271-46-4);(4aS
)-7-氯-2,5-二氫-2-[[(甲氧基羰基)[4-[(三氟甲基)硫基]苯基]胺基]羰基]-茚并[1,2-e][1,3,4]氧二氮雜環己烯-4a(3H
)-甲酸甲酯(自CN 102391261 A得知) (CAS 1370358-69-2);6-去氧-3-O
-乙基 -2,4-二-O
-甲基-、1-[N
-[4-[1-[4-(1,1,2,2,2-五氟乙氧基)苯基]-1H
-1,2,4-三唑-3-基]苯基]胺基甲酸酯]-α-L-吡喃甘露糖(自US 2014/0275503 A1得知) (CAS 1181213-14-8);8-(2-環丙基甲氧基-4-三氟甲基-苯氧基)-3-(6-三氟甲基-噠嗪-3-基)-3-氮雜-雙環[3.2.1 ]辛烷(CAS 1253850-56-4)、(8-抗)-8-(2-環丙基甲氧基-4-三氟甲基-苯氧基)-3-(6-三氟甲基-噠嗪-3-基)-3-氮雜-雙環[3.2.1 ]辛烷(CAS 933798-27-7)、(8-合成)-8-(2-環丙基甲氧基 -4-三氟甲基-苯氧基)-3-(6-三氟甲基-噠嗪-3-基)-3-氮雜-雙環[3.2.1 ]辛烷(自WO 2007040280 A1、WO 2007040282 A1得知) (CAS 934001-66-8)、N-[3-氯-1-(3-吡啶基)-1H-吡唑-4-基]-N-乙基-3-[(3,3,3-三氟丙基)硫基]-丙醯胺(自WO 2015/058021 A1、WO 2015/058028 A1已知) (CAS 1477919-27-9)、N-[4-(胺基硫氧基甲基)-2-甲基-6-[(甲胺基)羰基]苯基] -3-溴-1-(3-氯-2-吡啶基)-1H
-吡唑-5-甲醯胺(自CN 103265527 A得知) (CAS 1452877-50-7)、5-(1,3-二噁烷-2-基)-4-[[4-(三氟甲基)苯基]甲氧基]-嘧啶(自WO 2013/115391 A1得知) (CAS 1449021-97-9)、3-(4-氯 -2,6-二甲基苯基)-4-羥基-8-甲氧基-1-甲基-1,8-二氮螺[4.5]癸-3-烯-2-酮(自WO 2010/066780 A1、WO 2011/151146 A1得知) (CAS 1229023-34-0)、3-(4-氯-2,6-二甲基苯基)-8-甲氧基-1-甲基-1,8-二氮螺[4.5]癸烷-2,4-二酮(自WO 2014/187846 A1已知) (CAS 1638765-58-8)、3-(4-氯-2,6-二甲基苯基)-8-甲氧基-1-甲基-2-側氧基-1,8-二氮螺[4.5]癸-3-烯-4-基-碳酸乙酯(自WO 2010/066780 A1、WO 2011151146 A1得知) (CAS 1229023-00-0)、N-[1-[(6-氯-3-吡啶基)甲基]-2(1H
)-吡啶亞基]-2,2,2-三氟-乙醯胺(自DE 3639877 A1、WO 2012029672 A1得知) (CAS 1363400-41-2)、[N(E
)]-N-[1-[(6-氯-3-吡啶基)甲基]-2(1H)-吡啶亞基]-2,2,2-三氟-乙醯胺(自WO 2016005276 A1得知) (CAS 1689566-03-7)、[N(Z
)]-N-[1-[(6-氯 -3-吡啶基)甲基]-2(1H)-吡啶亞基]-2,2,2-三氟-乙醯胺(CAS 1702305-40-5)、3-內-3-[2-丙氧基-4-(三氟甲基)苯氧基]-9-[[5-(三氟甲基)-2-吡啶基]氧基]-9-氮雜雙環[3.3.1]壬烷(自WO 2011/105506 A1、WO 2016/133011 A1得知) (CAS 1332838-17-1)。
具有未知或非特異性作用模式之活性成分,例如芳氟胺(fentrifanil)、非諾克林(fenoxacrim)、環孢素(cycloprene)、乙酯殺蟎醇(chlorobenzilate)、殺蟲脒(chlordimeform)、氟蟎噻(flubenzimine)、地昔尼爾(dicyclanil)、安米氟美(amidoflumet)、甲基克殺蟎(quinomethionate)、苯蟎噻(triarathene)、氯噻苯(clothiazoben)、殺蟎好(tetrasul)、油酸鉀(potassium oleate)、石油(petroleum)、惡蟲酮(metoxadiazone)、棉紅鈴蟲性誘劑(gossyplure)、氟蟎嗪(flutenzin)、溴蟎酯(bromopropylate)、冰晶石(cryolite);
來自其他類別之活性成分,例如畜蟲威(butacarb)、敵蠅威(dimetilan)、地蟲威(cloethocarb)、磷蟲威(phosphocarb)、亞特松(pirimiphos)(乙基亞特松)、巴拉松(parathion)(乙基巴拉松)、蟲蟎畏(methacrifos)、鄰柳酸異丙酯、三氯松(trichlorfon)、硫丙磷(sulprofos)、丙蟲磷(propaphos)、克線丹(sebufos)、噠硫磷(pyridathion)、發硫磷(prothoate)、除線磷(dichlofenthion)、內吸磷-S-甲基碸(demeton-S-methylsulphone)、依殺松(isazofos)、苯腈磷(cyanofenphos)、氯亞胺硫磷(dialifos)、三硫磷(carbophenothion)、特嘧硫磷(autathiofos)、阿芬烯磷(aromfenvinfos)(甲基阿芬烯磷)、谷速松(azinphos)(乙基谷速松)、陶斯松(chlorpyrifos)(乙基陶斯松)、丁苯硫磷(fosmethilan)、碘硫磷(iodofenphos)、蔬果磷(dioxabenzofos)、安果(formothion)、地蟲磷(fonofos)、吡氟硫磷(flupyrazofos)、豐索磷(fensulfothion)、乙嘧硫磷(etrimfos);
有機氯,例如毒殺芬(camphechlor)、靈丹(lindane)、飛布達(heptachlor);或苯基吡唑,例如乙醯蟲腈(acetoprole)、氟蟲腈(pyrafluprole)、派瑞樂(pyriprole)、凡尼普羅(vaniliprole)、維吉黴素(sisapronil);或異噁唑啉(isoxazolines),例如薩洛拉納(sarolaner)、阿福拉納(afoxolaner)、洛替拉納(lotilaner)、弗拉拉納(fluralaner);
擬除蟲菊酯,例如(順式-擬除蟲菊酯、反式-擬除蟲菊酯)、甲氧苄氟菊酯(metofluthrin)、丙氟菊酯(profluthrin)、三氟醚(flufenprox)、溴氟菊酯(flubrocythrinate)、苄蟎醚(fubfenprox)、五氟苯菊酯(fenfluthrin)、丙苯烴菊酯(protrifenbute)、反滅蟲菊(pyresmethrin)、RU15525、環戊烯丙菊酯(terallethrin)、順式苄呋菊脂(cis-resmethrin)、右旋七氟甲醚菊酯(heptafluthrin)、戊環苄呋菊酯(bioethanomethrin)、生物氯菊酯(biopermethrin)、吡氯氰菊酯(fenpyrithrin)、順式-賽滅寧、順式百滅寧、三氟氯氰菊酯(clocythrin)、賽洛寧(λ-賽洛寧)、二氯炔戊菊酯(chlovaporthrin)或鹵化碳氫化合物(halogenated carbonhydrogen compound,HCH);
新菸鹼類似物,例如硝乙脲噻唑(nithiazine);
敵克美施(dicloromezotiaz)、三氟苯嘧啶(triflumezopyrim);
巨環內酯,例如尼莫克汀(nemadectin)、伊維菌素(ivermectin)、拉替菌素(latidectin)、莫昔克丁(moxidectin)、司拉克丁(selamectin)、依立諾克丁(eprinomectin)、多拉克汀(doramectin)、因滅汀苯甲酸酯(emamectin benzoate);米爾倍黴素肟(milbemycin oxime);
烯蟲硫酯(triprene)、保幼醚(epofenonane)、苯蟲醚(diofenolan);
生物製劑、激素或信息素,例如天然產物,例如蘇雲金素(thuringiensin)、蘋果小卷蛾性誘劑(codlemone)或印楝(neem)組分;
二硝基酚(dinitrophenols),例如白粉克(dinocap)、大脫蟎(dinobuton)、百蟎克(binapacryl);
苯甲醯基脲(benzoylureas),例如啶蜱脲(fluazuron)、氟幼脲(penfluron);
脒衍生物,例如滅蟎脒(chlormebuform)、賽米唑(cymiazole)、得米地曲(demiditraz);
蜂巢蜂殺蟎劑(Bee hive varroa acaricides),例如有機酸,例如甲酸、乙二酸。
用於動物健康狀況之備受關注之殺蟲劑及殺蟎劑之非限制性實例為且特定言之包括[亦即Mehlhorn等人, Encyclpaedic Reference of Parasitology 第4版 (ISBN 978-3-662-43978-4)]:
節肢動物配位體閘控氯離子通道處之效應子:氯丹(chlordane)、飛布達(heptachlor)、硫丹(endoculfan)、狄氏劑(Dieldrin)、溴烯殺(bromocyclen)、毒殺芬(toxaphene)、靈丹(lindane)、費普尼(fipronil)、派瑞樂(pyriprole)、維吉黴素(sisapronil)、阿弗索拉納(afoxolaner)、弗拉拉納、薩洛拉納(sarolaner)、洛替拉納(lotilaner)、氟唑醯胺(fluxametamide)、溴蟲氟苯雙醯胺(broflanilide)、阿巴汀(avermectin)、多拉克汀(doramectin)、依立諾克丁(eprinomectin)、伊維菌素(ivermectin)、米爾倍黴素(milbemycin)、莫昔克丁(moxidectin)、司拉克丁(selamectin);
節肢動物章魚胺激導性受體之調節劑:三亞蟎(amitraz)、BTS27271、賽米唑(cymiazole)、得米地曲(demiditraz);
節肢動物電壓閘控鈉通道處之效應劑:DDT、甲氧滴滴涕(methoxychlor)、氰氟蟲胺(metaflumizone)、因得克(indoxacarb)、瓜菊酯I (cinerin I)、瓜菊酯II、茉莉菊酯I (jasmolin I)、茉莉菊酯II、必列寧I(pyrethrin I)、必列寧II、丙烯除蟲菊酯、α賽滅寧(alphacypermethrin)、生物丙烯除蟲菊酯、保得寧(betacyfluthrin)、賽扶寧(cyfluthrin)、賽洛寧(cyhalothrin)、賽滅寧(cypermethrin)、第滅寧(deltamethrin)、依芬寧(etofenprox)、芬化利(fenvalerate)、護賽寧(flucythrinate)、氟氯苯菊酯(flumethrin)、苄蟎醚(halfenprox)、百滅寧(permethrin)、苯醚菊酯(phenothrin)、苄呋菊脂(resmethrin)、τ-福化利、治滅寧(tetramethrin);
節肢動物菸鹼膽鹼激導性突觸(乙醯膽鹼酯酶、乙醯膽鹼受體)之效應劑:溴蟎酯(bromoprypylate)、惡蟲威(bendiocarb)、加保利(carbaryl)、納乃得(methomyl)、蜱虱威(promacyl)、安丹(propoxur)、亞滅松(azamethiphos)、克芬松(chlorfenvinphos)、陶斯松(chlorpyrifos)、蠅毒磷(coumaphos)、畜蜱磷(cythioate)、大利松(diazinon)、二氯松(diclorvos)、雙特松(dicrotophos)、大滅松(dimethoate)、愛殺松(ethion)、伐滅磷(famphur)、撲滅松(fenitrothion)、芬殺松(fenthion)、庚烯磷(heptenophos)、馬拉硫磷、二溴磷(naled)、益滅松(phosmet)、巴賽松(phoxim)、捷利康(phtalofos)、巴胺磷(propetamphos)、雙硫磷(temephos)、樂本松(tetrachlorvinphos)、三氯松(trichlorfon)、吡蟲啉(imidacloprid)、烯啶蟲胺(nitenpyram)、呋蟲胺(dinotefuran)、賜諾殺(spinosad)、斯平托蘭(spinetoram);
節肢動物發育過程之效應劑:賽滅淨(cyromazine)、地昔尼爾(dicyclanil)、二福隆(diflubenzuron)、啶蜱脲(fluazuron)、祿芬隆(lufenuron)、三福隆(triflumuron)、芬諾克(fenoxycarb)、烯蟲乙酯(hydroprene)、美賜平(methoprene)、百利普芬(pyriproxyfen)、芬諾克(fenoxycarb)、烯蟲乙酯(hydroprene)、S-美賜平(S-methoprene)、百利普芬(pyriproxyfen)。
作為在本發明中之另一或其他活性成分的來自殺內寄生蟲藥之群的例示性活性成分包括(但不限於)驅蟲活性化合物及抗原蟲活性化合物。
驅蠕蟲活性化合物包括(但不限於)以下殺線蟲(nematicidally)、殺吸蟲(trematicidally)及/或殺緣蟲(cestocidally)活性化合物:
來自巨環內酯類,例如:依立諾克丁(eprinomectin)、阿巴汀(abamectin)、尼莫克汀(nemadectin)、莫昔克丁(moxidectin)、多拉克汀(doramectin)、司拉克丁(selamectin)、林皮沒丁(lepimectin)、拉替菌素(latidectin)、密滅汀(milbemectin)、伊維菌素(ivermectin)、因滅汀(emamectin)、米爾倍黴素(milbemycin);
來自苯并咪唑及樸苯并咪唑(probenzimidazole)類,例如:奧苯達唑(oxibendazole)、甲苯達唑(mebendazole)、三氯苯咪唑(triclabendazole)、多保淨(thiophanate)、帕苯達唑(parbendazole)、奧芬達唑(oxfendazole)、尼妥必敏(netobimin)、芬苯達唑(fenbendazole)、非班太爾(febantel)、噻苯達唑(thiabendazole)、環苯達唑(cyclobendazole)、坎苯達唑(cambendazole)、阿苯達唑-亞碸(albendazole-sulphoxide)、阿苯達唑(albendazole)、氟苯達唑(flubendazole);
來自縮肽、較佳環狀縮肽類,特定言之24員環狀縮肽,例如:艾默德斯(emodepside)、PF1022A;
來自四氫嘧啶類,例如:莫侖太(morantel)、噻嘧啶(pyrantel)、奧克太爾(oxantel);
來自咪唑并噻唑類,例如:丁咪唑(butamisole)、左旋咪唑(levamisole)、四咪唑(tetramisole);
來自胺基苯脒類,例如:阿米登太(amidantel)、去醯化阿米登太(dAMD)、三苯雙脒(tribendimidine);
來自胺基乙腈類,例如:莫尼特爾(monepantel);
來自帕拉米德(paraherquamide)類,例如:帕拉米德、德曲安特(derquantel);
來自柳醯苯胺類,例如:三溴沙侖(tribromsalan)、溴沙尼特(bromoxanide)、溴替尼特(brotianide)、氯碘沙尼(clioxanide)、氯氰碘柳胺(closantel)、氯硝柳胺(niclosamide)、羥氯紮胺(oxyclozanide)、碘醚柳胺(rafoxanide);
來自經取代之苯酚類,例如:硝羥碘苄腈(nitroxynil)、硫雙二氯酚(bithionol)、二碘硝酚(disophenol)、六氯酚(hexachlorophene)、聯硝氯酚(niclofolan)、聯硝氯酷(meniclopholan);
來自有機磷酸酯類,例如:三氯松、萘肽磷(naphthalofos)、二氯松/DDVP、育畜磷(crufomate)、蠅毒磷、哈洛克酮(haloxon);
來自哌嗪酮/喹啉類,例如:吡喹酮(praziquantel)、依西太爾(epsiprantel);
來自哌嗪類,例如:哌嗪、羥嗪(hydroxyzine);
來自四環素類,例如:四環素(tetracyclin)、金黴素(chlorotetracycline)、脫氧土黴素(doxycyclin)、土黴素(oxytetracyclin)、羅列環素(rolitetracyclin);
來自其他不同類別,例如:丁萘脒(bunamidine)、硝噻噠唑(niridazole)、溴二羥苯醯苯胺(resorantel)、奧弗亭(omphalotin)、奧替普拉(oltipraz)、硝異硫氰二苯醚(nitroscanate)、氮氧尼(nitroxynile)、奧沙尼喹(oxamniquine)、米拉桑(mirasan)、鹽酸盧甘宋(miracil)、胺甲硫蒽酮(lucanthone)、羥胺硫蒽酮(hycanthone)、三氯苯丙醯嗪(hetolin)、吐根素(emetine)、二乙碳醯嗪(diethylcarbamazine)、二氯酚(dichlorophen)、地芬尼泰(diamfenetide)、氯硝西泮(clonazepam)、酚乙銨(bephenium)、硝硫氰胺(amoscanate)、氯舒隆(clorsulon)。
在本發明中,抗原蟲活性成分包括(但不限於)以下活性成分:
來自三嗪類,例如:地克珠利(diclazuril)、泊那珠利(ponazuril)、來曲珠利(letrazuril)、托曲珠利(toltrazuril);
來自聚醚離子載體類,例如:莫能菌素(monensin)、鹽黴素(salinomycin)、馬杜黴素(maduramicin)、那拉黴素(narasin);
來自巨環內酯類,例如:米爾倍黴素(milbemycin)、紅黴素(erythromycin);
來自喹諾酮類,例如:恩氟沙星(enrofloxacin)、普多沙星(pradofloxacin);
來自奎寧類,例如:氯奎(chloroquine);
來自嘧啶類,例如:乙胺嘧啶;
來自磺醯胺類,例如:磺胺喹噁啉(sulfaquinoxaline)、甲氧苄啶(trimethoprim)、磺胺氯吡嗪(sulfaclozin);
來自硫胺類,例如:安普羅利(amprolium);
來自林可醯胺(lincosamides)類,例如:克林達黴素(clindamycin);
來自對稱二苯脲類,例如:咪多卡(imidocarb);
來自硝基呋喃(nitrofuranes)類,例如:硝呋莫司(nifurtimox);
來自喹唑啉酮生物鹼類,例如:鹵夫酮(halofuginon);
來自其他不同類,例如:羥胺硝喹(oxamniquin)、巴龍黴素(paromomycin);
來自微生物之疫苗或抗原類,例如:羅氏犬巴貝斯蟲(Babesia canis rossi)、柔嫩艾美耳球蟲(Eimeria tenella)、早熟艾美耳球蟲(Eimeria praecox)、毒害艾美球蟲(Eimeria necatrix)、和緩艾美耳球蟲(Eimeria mitis)、巨型艾美爾球蟲(Eimeria maxima)、布氏艾美球蟲(Eimeria brunetti)、堆形艾美耳球蟲(Eimeria acervulina)、韋氏巴貝斯蟲(Babesia canis vogeli)、嬰兒利什曼原蟲(Leishmania infantum)、犬巴倍蟲屬(Babesia canis canis)、網尾線蟲屬(Dictyocaulus viviparus)。
本發明中之所有指定的其他或另外活性成分若其官能基能夠實現此目的,則可視情況與適合鹼或酸形成鹽。
基於已知用於評估適用於治療蠕蟲感染之化合物的標準實驗室技術,藉由標準毒性測試及藉由用於測定對動物之以上所鑑別之病狀之治療的標準藥理學分析,且藉由比較此等結果與用於治療此等病狀之已知活性成分或藥物之結果,可容易地測定用於治療各種所要適應症之本發明化合物的有效劑量。治療此等病況中之一者所投與之活性成分之量可根據諸如以下考慮因素而廣泛變化:所用特定化合物及劑量單位、投與模式、治療週期、所治療個體之年齡及性別,及所治療病況之性質及程度。
所投與活性成分之總量一般將介於每日約0.001 mg/kg至約200 mg/kg體重且較佳地每日約0.01 mg/kg至約20 mg/kg體重。臨床上有用之給藥時程之範圍將為一天給藥一至三次至每四週給藥一次。另外,「藥物假期」(其中在一定時間段內不向個體給與藥物)有可能有益於藥理學效應與耐受性之間的整體平衡。另外,有可能具有長效治療,其中該個體接受治療一次持續超過四週。單位劑型可能含有約0.5 mg至約1500 mg活性成分,且可每日投與一或多次或每日投與少於一次。藉由注射(包括靜脈內、肌肉內、皮下及非經腸注射)及使用輸注技術投與之每日平均劑量較佳地為0.01至200 mg/kg總體重。平均每日經直腸給藥方案較佳地為0.01至200 mg/kg總體重。平均每日經陰道給藥方案較佳將為0.01至200 mg/kg總體重。平均每日局部給藥方案較佳將為0.1至200 mg,每日投與一次至四次。透皮濃度較佳地將為維持0.01至200 mg/kg日劑量所需之濃度。平均每日吸入給藥方案較佳地為0.01至100 mg/kg總體重。
當然,各個體之特定初始及連續給藥方案將根據以下因素而變:如主治診斷醫師所確定之病況性質及嚴重程度、所用特定化合物之活性、個體之年齡及一般狀況、投與時間、投與途徑、藥物之排泄速率、藥物組合及其類似因素。所需治療模式及本發明化合物或其醫藥學上可接受之鹽或酯或組合物的劑量數可由熟習此項技術者使用習知治療測試來判定。
實驗部分
縮寫及首字母縮寫詞
aq. 水溶液
atm 標準大氣
DAD 二極體陣列偵測器
DMF 二甲基甲醯胺
DMSO 二甲亞碸
ELSD 蒸發光散射偵測器
ESI 電噴霧電離
h 小時
LC-MS 液相層析偶合質譜分析
min 分鐘
MTBE 甲基-第三丁基醚
NMR 核磁共振光譜法
p. 頁
Rt
滯留時間
THF 四氫呋喃
TLC 薄層層析法
本申請案中所描述之本發明之各種態樣藉由以下實例來說明,該等實例不以任何方式限制本發明。
本文所描述之實例測試實驗用以說明本發明且本發明不限於所給出之實例。
實驗部分 - 綜述部分
其合成未描述於實驗部分中的所有試劑均可商購,或為已知化合物,或可由熟習此項技術者利用已知方法由已知化合物形成。
根據本發明方法產生之化合物及中間物可能需要純化。有機化合物之純化為熟習此項技術者所熟知且可存在純化同一化合物之數種方法。在一些情況下,可不必純化。在一些情況下,化合物可藉由結晶來純化。在一些情況下,可使用適合溶劑攪拌去雜質。在一些情況下,化合物可藉由層析,尤其急驟管柱層析使用例如預填充矽膠筒(例如Biotage SNAP筒KP-Sil®
或KP-NH®
)以及Biotage自動純化器系統(SP4®
或Isolera Four®
)及溶離劑(諸如己烷/乙酸乙酯或DCM/甲醇之梯度)來純化。在一些情況下,化合物可藉由製備型HPLC使用例如配備有二極體陣列偵測器及/或聯機電噴霧電離質譜儀之Waters自動純化器與適合之預填充逆相管柱及可含有添加劑(諸如三氟乙酸、甲酸或氨水)的諸如水及乙腈之梯度的溶離劑組合來純化。
在一些情況下,如上文所描述之純化方法可提供具有充分鹼性或酸性官能基、呈鹽形式的本發明之彼等化合物,諸如為充分鹼性之本發明化合物的情況下,例如呈三氟乙酸鹽或甲酸鹽形式;或為充分酸性之本發明化合物的情況下,例如呈銨鹽形式。此類型之鹽可藉由熟習此項技術者所已知之多種方法而分別轉化為其游離鹼或游離酸形式,或在隨後生物分析中用作鹽。應理解,如分離且如本文所描述之本發明化合物的特定形式(例如鹽、游離鹼等)未必為該化合物可應用於生物分析以便量化特定生物活性的唯一形式。
分析及層析方法分析及製備型液相層析
藉助於如下所述之不同設備來執行分析型(UP)LC-MS。除非指定負模式(ESI-),否則報導正模式電噴霧電離的質量(m/z)。
LC-MS 方法 0 :
藉由以下方法在逆相管柱上藉由HPLC (高效液相層析法)根據EEC指令79/831 AnnexV.A8執行logP值之量測,儀器:Agilent 1100 LC系統、Agilent MSD系統,HTS PAL;Waters IClass Acquity UPLC, SQD2 (MS), PDA (UV)。[a]
logP值藉由在酸性範圍中用含0.1%甲酸之水及乙腈作為溶離劑(10%乙腈至95%乙腈之線性梯度)進行LC-UV之量測來測定的。[b]
LogP值藉由在中性範圍中用含0.001莫耳乙酸銨溶液之水及乙腈作為溶離劑(10%乙腈至95%乙腈之線性梯度)進行LC-UV之量測來測定。
在已知logP值(使用滯留時間及在連續烷酮之間的線性內插值量測logP值)下用直鏈烷-2-酮(具有3至16個碳原子)進行校準。使用200 nm至400 nm之UV光譜及層析信號之峰值測定λ最大值。
M+1(或M+H)意謂分子態離子峰值分別±1原子質量單元(atomic mass unit,a.m.u.),如藉由電噴霧電離(ESI+或-)在質譜分析中觀測到。
LC-MS 方法 1 :
MS儀器類型:Agilent Technologies 6130 Quadrupole LC-MS;HPLC儀器類型:Agilent Technologies 1260 Infinity;管柱:Waters XSelect (C18, 30×2.1mm, 3.5μ);流量:1 mL/min;管柱溫度35℃;溶離劑A:含0.1%甲酸之乙腈;溶離劑B:含0.1%甲酸之水;線性梯度:t=0 min 5% A,t=1.6 min 98% A,t=3 min 98% A;偵測:DAD (220-320 nm);偵測:MSD (ESI正/負)質量範圍:100 - 800;偵測:ELSD (PL-ELS 2100):氣體流速1.2 mL/min,氣體溫度:70℃,neb:50℃。
LC-MS 方法 2 :
儀器類型:Waters ACQUITY SQD UPLC系統;管柱:Waters Acquity UPLC HSS T3 1.8 µ 50 × 1 mm;溶離劑A:1 l水+ 0.25 ml 甲酸,溶離劑B:1 l乙腈+ 0.25 ml甲酸;梯度:0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A,烘箱:50℃;流量:0.40 ml/min;UV偵測:210 nm。
LC-MS 方法 3 :
MS儀器類型:Agilent Technologies LC/MSD SL;HPLC儀器類型:Agilent Technologies 1100系列;管柱:Waters XSelect (C18, 30×2.1mm, 3.5μ);流速:1 mL/min;管柱溫度:25℃;溶離劑A:含95%乙腈+ 5% 10 mM碳酸氫銨之水;溶離劑B:含10 mM碳酸氫銨之水 pH=9.0;線性梯度:t=0 min 5% A,t=1.6 min 98% A,t=3 min 98% A;偵測:DAD (220-320 nm);偵測:MSD (ESI正/負)質量範圍:100-800。
LC-MS 方法 4 :
儀器類型:Waters ACQUITY SQD UPLC系統;管柱:Waters Acquity UPLC HSS T3 1.8 µ 50×1 mm;溶離劑A: 1 l水+ 0.25 ml 99%ige甲酸,溶離劑B: 1 l乙腈+ 0.25 ml 99%ige甲酸;梯度:0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A ,烘箱:50℃;流量:0.35 ml/min;UV偵測:210 nm。
LC-MS 方法 5
:
儀器類型:來自Waters之具有SQD2及Sample Manager之UPLC,管柱:Zorbax Eclipse Plus C18,50 mm×2.1 mm、1.8 µm,溶離劑A:1 l乙腈+1 ml甲酸,溶離劑B:1 l水+0.9 ml甲酸;梯度0.0 min 90% B → 1.7 min 5% B → 2.4 min 5% B,DAD A:210±4 nm,參考360±50 nm,DAD A:270±2 nm,參考550±50 nm(僅酮),MSD 100-1000 Amu,ES電離,正極或負極。
1 H-NMR 資料 1
H-NMR資料係藉由四甲基矽烷作為參考(0.0)及溶劑CD3
CN、CDCl3
或D6
-DMSO由以下設備測定:Bruker Avance 400 (配備有流槽(60 μl體積)、或配備有1.7 mm低溫CPTCI探頭之Bruker AVIII 400、或配備有5 mm探頭之Bruker AVIII 400 (400.13MHz)、或配備有5 mm低溫TCI探頭之Bruker AVII 600 (600.13 MHz)、或配備有5 mm低溫CPMNP探頭之Bruker AVIII 600 (601.6 MHz)、或配備有5 mm寬帶頭或5 mm Prodigy™探頭之Bruker AVIII 500 (500.13MHz)、或Bruker Avance NEO 600 MHz (5 mm TCI低溫探頭)。替代1
H-及13
C-NMR儀器類型:Bruker DMX300 (1
H-NMR: 300 MHz;13
C NMR: 75 MHz)、Bruker Avance III 400 (1
H-NMR: 400 MHz;13
C NMR: 100 MHz)或Bruker 400 Ultrashield (1
H-NMR: 400 MHz;13
C NMR: 100 MHz)。
化學位移(δ)以百萬分率[ppm]顯示;使用以下縮寫:s=單峰,d=雙重峰,t=三重峰,q=四重峰,m=多重峰,br.=寬峰;偶合常數以赫茲[Hz]顯示。
實驗部分-通用程序 式(I)化合物之合成可根據或類似於以下流程(流程1、流程2、流程3、流程4及流程5)執行。
流程 1 :
經2-鹵素取代之苯胺1A
(Hal =碘、溴、氯)為可商購的且可容易與(烷氧基亞甲基)丙二酸酯1B
,如Monatshefte fuer Chemie, 2015, 146(2), 291-302中所描述溶解於相應醇溶劑,較佳地在煮沸條件下或如WO 2002004444中所描述在無任何溶劑下轉化為(苯胺基亞甲基)丙二酸酯1C
。環閉合在高沸點溶劑中,較佳地在二苯基醚或二甲苯中執行,以獲得羥基喹啉1D
,如WO 2013118071中所描述。羥基喹啉1D
可容易地藉由氯化試劑,較佳地回流POCl3
而轉化為對應氯化合物1E
,如WO 2013118071中所描述。
視親核試劑R2
H1F
之性質而定,氯喹啉1E
與1F
在例如乙醇鈉、甲醇鈉、第三丁醇鉀、三乙胺N,N
-二異丙基乙胺、二氮二環十一烷、氫化鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸銫或其類似物之鹼存在下反應,獲得酯中間物1G
。
視金屬有機試劑2A
及鹵素而定,鹵素喹啉1E
視需要在存在如Tetrahedron Letters 39 (1998), 第6163-6166頁中所描述的催化劑(例如鈷鹽)的情況下與鋅試劑反應,或在存在如Angew. Chem., 2014,第126卷,第12975-12978頁或European Journal of Medicinal Chemistry;第147卷; (2018); 第238-252頁中所描述之鈀催化劑的情況下與格林納試劑或酸或其酯2P
(R=H;R=Me或R,R=頻哪醇酯)反應,獲得中間物1G
。
酯中間物1G
可容易地在諸如乙醇或環醚之合適溶劑中藉由例如氫氧化鈉或氫氧化鋰水溶液而水解為對應酸1S
。可經由醯胺形成及脫水試劑,例如N-(
3-二甲胺基異丙基)-N'
-乙基碳化二亞胺-鹽酸鹽(EDC)或2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物使酸1S
與可商購之胺1M
反應,得到醯胺I-a
。類似合成描述於例如Journal of Medicinal Chemistry 2012, 55, 第3563-3567頁或Chem. Commun. 1999, 第1847-1848頁中。
中間物甲醯胺I-a
與酸或酸酯1H
Q-B(OR)2
(R=H;R = Me或R,R =頻哪醇酯)之鈴木(Suzuki
)交叉偶合反應,如Chem. Soc. Rev. 2014, 43,第412-443頁中或Tetrahedron 2002, 58 (48),第9633-9695頁中所述,產生式(I)
之最終產物。
可經由醯胺形成及脫水試劑,例如N-(
3-二甲胺基異丙基)-N'
-乙基碳化二亞胺-鹽酸鹽(EDC)或2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物使酸1R
與可商購之胺1M
反應,得到醯胺1N
。類似合成描述於例如Journal of Medicinal Chemistry 2012, 55, 第3563-3567頁或Chem. Commun. 1999, 第1847-1848頁中。鹵代中間物1N
可在存在鈀催化劑的情況下與烯系酸酯2P (R=Me或R,R=頻哪醇酯)偶合,如WO 200537826中所報導。烯系殘基可在標準條件下,例如藉由氫/鈀/木炭而氫化為(I)
。若在喹啉核上出現進一步還原,則此類還原產物,例如二氫喹啉中間物可藉由(例如)含鈰-(IV)-鹽之合適溶劑,例如DMSO及水或乙腈及水之混合物而再氧化成喹啉酮,得到(I)
。
酯中間物1G
與酸或酸酯1H
Q-B(OR)2
(R=H;R = Me或R,R =頻哪醇酯)之鈴木交叉偶合反應,如Chem. Soc. Rev. 2014, 43,第412-443頁或Tetrahedron 2002, 58 (48), 第9633-9695頁中所描述,產生酯中間物1T
,其可隨後在諸如乙醇或環醚之合適溶劑中藉由例如氫氧化鈉或氫氧化鋰水溶液而經水解成對應酸1R
。
流程 2 :
替代地,中間物1D
與酸或酸酯1H
Q-B(OR)2
(R=H;R=Me或R,R=頻哪醇酯)之鈴木交叉偶合反應,如Chem. Soc. Rev. 2014, 43, 第412-443頁中或Tetrahedron 2002, 58 (48), 第9633-9695頁中所述,得到酯中間物1I
。隨後,酯中間物1I
可例如藉由氫氧化鈉或氫氧化鋰經光滑地皂化,產生對應羧酸1J
,其可藉由鹵化試劑,例如POCl3
或POBr3
(較佳地回流POCl3
)而容易地轉換為對應氯基甲酸氯化物1K
,如WO 2013096151中所描述。中間物1K
在水解條件下反應以產生喹啉羧酸1L
,其經由醯胺形成及脫水試劑(例如N-
(3-二甲胺基異丙基)-N'
-乙基碳化二亞胺-鹽酸鹽(EDC)或2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物)與可商購之胺1M
組合,得到醯胺1N
。類似合成描述於例如Journal of Medicinal Chemistry 2012, 55, 第3563-3567頁或Chem. Commun. 1999, 第1847-1848頁中。當羧酸氯化物1K
與胺1M
在例如吡啶、三乙胺或N,N
-二異丙基乙胺之鹼性條件下組合時,中間物1K
可直接形成醯胺1N
,如Chemical Biology & Drug Design 2015, 85(5), 第549-564頁中所述。
視親核試劑R2
H1F
之性質而定,氯喹啉1N
與1F
在例如乙醇鈉、甲醇鈉、第三丁醇鉀、三乙胺N,N-二異丙基乙胺、二氮二環十一烷、氫化鈉、氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸銫或其類似物之鹼存在下反應,獲得目標式(I)
化合物。
流程 3 :
酯中間物1Q
可在諸如乙醇或環醚之合適溶劑中藉由例如氫氧化鈉或氫氧化鋰水溶液而容易地水解成對應酸1R
。可經由醯胺形成及脫水試劑,例如N
-(3-二甲胺基異丙基)-N'
-乙基碳化二亞胺-鹽酸鹽(EDC)或2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物使酸1R
與可商購之胺1M
反應,得到醯胺1N
。類似合成描述於例如Journal of Medicinal Chemistry 2012, 55, 第3563-3567頁或Chem. Commun. 1999, 第1847-1848頁中。鹵素中間物1N
可在存在鈀催化劑之情況下與烯系酸酯1P
(R=Me或R,R=頻哪醇酯;R21
、R22
、R23
為C1
-C3
烷基或形成二氫哌喃基環)偶合,如例如WO 200537826中所報導。烯系殘基可在標準條件下,例如藉由氫/鈀/木炭而氫化為(I)
。若在喹啉核上出現進一步還原,則此類還原產物,例如二氫喹啉中間物可藉由(例如)含鈰-(IV)-鹽之合適溶劑,例如DMSO及水或乙腈及水之混合物而再氧化成喹啉酮,得到(I)
。
流程 4 :
替代地,若R2
攜帶有至少一個氫原子且W
為CH活化基團,例如酯或氰基,則氯喹啉1E
可在存在鹼(例如六甲基矽氮烷鋰、氫化鈉或第三丁酸鉀)的情況下經基團W-R2
取代,產生1G
。舉例而言,類似反應描述於Org. Proc. Res.及Dev. 2001, 5, 第28-36頁或WO 2013174780中。在酯1G
之皂化期間,可藉由皂化及去羧基順序使基團W
分裂,產生酸1X
。利用酸1X
,可藉由如上文所描述之醯胺形成反應容易地獲得醯胺中間物I-a
。
流程 5 :
替代地,7-氟喹林1G
(R4
= F)可藉由在高溫下用醇、鹼及一些水處理而轉化為7-烷氧基-喹啉羧酸1S
(R4
=C1
-C4
烷氧基)。
最終產物(I)
可藉由如上文所描述之相同反應合成。
在上文所描述之流程1至5中,除非另外明確描述,否則Q、A、R1
、R2
、R3
、R4
、R5
及R6
具有如上文所定義之含義。
NMR峰清單 NMR峰形式如譜圖中所示,尚未考慮可能的高階效應。
所選實例之1
H-NMR資料以1
H-NMR峰清單之形式書寫。對於各信號峰,所列δ值以ppm表示且信號強度在圓括號中表示。δ值-信號強度對之間係作為分隔符之分號或逗號。
因此,實例之峰清單具有以下形式:
δ1
(強度1
);δ2
(強度2
);……..; δi
(強度i
);……;δn
(強度n
)或
δ1
(強度1
),δ2
(強度2
),……..; δi
(強度i
),……,δn
(強度n
)
在所印刷之NMR波譜實例中,尖銳信號之強度與信號高度(cm)相關且顯示信號強度之真實關係。根據寬信號,可顯示信號之若干峰值或中間值及其相比於光譜中之最密集信號之相對強度。
為針對1
H光譜校準化學位移,吾人使用四甲基矽烷及/或所用溶劑之化學位移,在DMSO中量測之光譜之情況下尤其如此。因此,在NMR峰清單中,四甲基矽烷峰可能但不一定出現。
1
H-NMR峰清單類似於經典1
H-NMR印刷圖且因此通常含有經典NMR解釋處所列之所有峰。
另外,其可如經典1
H-NMR印刷圖一樣顯示溶劑信號、目標化合物之立體異構體(其亦為本發明之目的)及/或雜質之峰。
為在溶劑及/或水之δ範圍(delta-range)中顯示化合物信號,常用溶劑之峰(例如含DMSO之DMSO-D6
中之峰及水之峰)顯示於吾人之1
H-NMR峰清單中且通常具有平均之高強度。
目標化合物之立體異構體之峰及/或雜質之峰通常具有平均比目標化合物(例如具有大於90%之純度)之峰低的強度。
此類立體異構體及/或雜質對於特定製備方法可為典型的。因此其峰可經由「副產物指紋」幫助辨認吾人之製備方法之再現。
用已知方法(MestreC、ACD模擬,以及用憑經驗評估之期望值)計算目標化合物之峰的專家可視情況使用另外的強度過濾器按需要分離目標化合物之峰。此分離將類似於經典1
H-NMR解釋處之相關峰挑選。
具有峰清單之NMR資料描述的其他詳情見於研究揭示資料庫編號564025之公開案「Citation of NMR Peaklist Data within Patent Applications」中。
中間物
中間物1A
4-羥基-8-(2,3,5-三氟苯基)喹啉-3-甲酸
8-溴-4-羥基喹啉-3-甲酸乙酯(5.00 g, 16.89 mmol) (Zask等人 Bioorganic and Medicinal Chemistry Letters, 2003, 1487-1490;Gharat等人 WO/2013/118071)、(2,3,5-三氟苯基)酸(3.56 g, 20.26 mmol)及氟化鉀(2.94 g, 50.70 mmol)於四氫呋喃(50 mL)及水(5 mL)中之混合物藉由氮氣充氣持續10 min。在添加參(二亞苄基丙酮)二鈀(0) (0.77 g, 0.84 mmol)及三-第三丁基膦四氟硼酸酯(0.49 g, 1.69 mmol)後,反應混合物藉由氮氣充氣持續10 min並在75℃下攪拌18 h。隨後添加水(25 mL)及單水合氫氧化鋰(3.54 g, 84 mmol)且在90℃下攪拌反應混合物4 h。在添加水(35 mL)及單水合氫氧化鋰(3.54 g, 84 mmol)後,在90℃下攪拌持續18 h。使反應混合物冷卻至室溫。添加活性炭(2 g)且攪拌混合物1 h。在矽藻土墊上濾出固體。用氫氧化鈉水溶液(1 M; 3×30 mL)及四氫呋喃(3×30 mL)洗滌濾餅。將濾過物緩慢添加至氫氯酸(1 M; 300 mL)中。攪拌所得懸浮液30 min。將沈澱物濾出,用水及乙醚洗滌並在空氣中乾燥。獲得5.33 g (99%理論值)標題化合物。
LC-MS (方法1):Rt
= 1.92 min; m/z = 320 (M+H)+ 1
H-NMR (400 MHz, DMSO-d
6) δ 15.11 (s, 1H), 12.35 (s, 1H), 8.58 (s, 1H), 8.46 (dd, 1H), 7.91 (dd, 1H), 7.86 - 7.77 (m, 1H), 7.73 (t, 1H), 7.44 - 7.36 (m, 1H).
中間物 2A
4-氯-8-(2,3,5-三氟苯基)喹啉-3-甲醯基氯化物
在氮氣氛圍下,在室溫下,將4-羥基-8-(2,3,5-三氟苯基)喹啉-3-甲酸(5.33 g, 17 mmol)添加至氧氯化磷(8.0 mL, 86 mmol)中。在110℃下攪拌懸浮液2.5 h。使反應混合物冷卻至室溫。在40℃下真空移除揮發物。將殘餘黑色油儲存在氬氣下且按原樣使用。
LC-MS (方法1):Rt
= 2.24 min; m/z = 352 (M+H)+
[針對對應甲基酯]
中間物 3A
4-氯-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
在0℃之氬氣氛圍下,向粗製4-氯-8-(2,3,5-三氟苯基)喹啉-3-甲醯氯(17 mmol)於乾燥四氫呋喃(30 mL)中之溶液中添加N,N-二異丙基乙胺(15 mL, 84 mmol)。攪拌混合物10 min且逐份添加(S)-𠳭烷-4-胺鹽酸鹽(3.13 g, 17 mmol)。使反應混合物升溫至室溫並攪拌74 h。添加活性炭(2 g)並攪拌混合物30 min。在矽藻土墊上濾出固體。用四氫呋喃(3×30 mL)洗滌濾餅。在0℃,將濾過物緩慢添加至氫氯酸(1 M; 150 mL)中。攪拌所得懸浮液30 min。濾出固體,用水洗滌,在空氣中乾燥二異丙基醚及甲基-第三丁基醚。獲得5.41 g (69%理論值)標題化合物。
LC-MS (方法3):Rt
= 2.21 min; m/z = 469/471 (M+H)+
1H NMR (400 MHz, DMSO-d
6) δ 9.29 (d, 1H), 8.93 (s, 1H), 8.45 (dd, 1H), 8.02 - 7.91 (m, 2H), 7.74 - 7.56 (m, 1H), 7.38 (dd, 1H), 7.34 - 7.26 (m, 1H), 7.18 (td, 1H), 6.93 (td, 1H), 6.80 (dd, 1H), 5.28 (dt, 1H), 4.33 - 4.20 (m, 2H), 2.27 - 2.17 (m, 1H), 2.12 - 2.02 (m, 1H).
中間物 4A
8-溴-4-[4-(甲氧基羰基)四氫-2H-哌喃-4-基]喹啉-3-甲酸乙酯
在氬氣下,四氫-2H-哌喃-4-甲酸甲酯(3.2 ml, 24 mmol)於THF (32 ml)中之溶液係在-5℃下用雙-(三甲基矽烷基)-鋰胺(29 ml, 含1.0 M溶液之THF, 29 mmol)處理,且在-5℃至0℃下攪拌10 min。隨後在此溫度下逐份添加固體8-溴-4-氯喹啉-3-甲酸乙酯(5.0 g, 15.9 mmol) (Zask等人. Bioorganic and Medicinal Chemistry Letters, 2003 , 1487-1490;Gharat等人 WO/2013/118071)且在-5℃下攪拌持續30 min。使反應混合物升溫至室溫。在45 min後,將混合物逐份添加至水(250 ml)及乙酸(3.3 ml, 58 mmol)之攪拌混合物中。藉由在降低壓力下蒸發來移除THF且用乙酸乙酯萃取水性混合物。乾燥且蒸發有機相。藉由急驟層析在二氧化矽(100 g)上利用環己烷/乙酸乙酯(12-17%)純化殘餘物。
產量:5.44 g (98%純,79%理論值)
LC-MS (方法2):Rt
= 1.07 min; MS (ESIpos): m/z = 422 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.357 (6.88), 1.375 (14.95), 1.393 (7.58), 1.397 (4.39), 2.179 (0.88), 2.200 (1.86), 2.213 (1.51), 2.220 (1.36), 2.233 (2.39), 2.254 (1.26), 2.414 (3.29), 2.447 (2.46), 3.310 (16.00), 3.820 (6.73), 3.838 (6.62), 3.966 (0.97), 4.110 (1.06), 4.431 (2.21), 4.449 (6.96), 4.467 (6.93), 4.485 (2.15), 5.755 (2.36), 7.591 (2.17), 7.610 (2.77), 7.613 (2.73), 7.632 (2.40), 8.184 (3.11), 8.205 (2.76), 8.206 (2.77), 8.224 (3.20), 8.242 (3.07), 8.911 (7.68).
中間物 5A
8-溴-4-(四氫-2H-哌喃-4-基)喹啉-3-甲酸
8-溴-4-[4-(甲氧基羰基)四氫-2H-哌喃-4-基]喹啉-3-甲酸乙酯(845 mg, 2.0 mmol)在含有氫氧化鈉水溶液(2.4 ml, 5 M, 12 mmol)之異丙醇(8 ml)中回流2天。在50℃下逐滴添加水(15 ml)及氫氯酸(3 ml, 5 M, 15 mmol)。在環境溫度下攪拌所形成懸浮液3h,過濾出沈澱物,用水/異丙醇(2:1)洗滌且在真空中乾燥。
產量:691 mg (> 100%理論值,粗物質)
LC-MS (方法4): Rt
= 1.88 min; MS (ESIpos): m/z = 336 [M+H]+
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.50), 0.006 (1.00), 1.034 (1.53), 1.046 (1.51), 1.678 (4.44), 1.699 (4.80), 2.348 (1.15), 2.357 (1.43), 2.373 (3.28), 2.381 (3.40), 2.398 (3.41), 2.406 (3.20), 2.423 (1.35), 2.431 (1.19), 3.526 (3.52), 3.547 (6.66), 3.570 (3.67), 3.906 (0.86), 3.913 (1.53), 3.920 (1.03), 3.931 (1.74), 3.938 (2.90), 3.945 (1.68), 3.955 (1.01), 3.962 (1.46), 3.970 (0.81), 3.998 (4.92), 4.006 (5.13), 4.021 (4.63), 4.029 (4.38), 7.606 (4.83), 7.621 (6.26), 7.623 (5.84), 7.638 (5.05), 8.223 (7.00), 8.225 (6.80), 8.238 (7.01), 8.525 (5.52), 8.542 (5.36), 8.685 (0.47), 8.987 (16.00), 13.845 (0.91).
中間物 6A
8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(四氫-2H-哌喃-4-基)喹啉-3-甲醯胺
將8-溴-4-(四氫-2H-哌喃-4-基)喹啉-3-甲酸(690 mg, 2.05 mmol)於DMF/THF (1:3混合物, 14 ml)中之溶液置於55℃之油浴中並用(4S)-𠳭烷-4-胺鹽酸鹽(457 mg, 2.46 mmol)及N,N-二異丙基乙胺(1.4 ml, 8.2 mmol)處理。移除加熱並逐滴添加2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物於乙酸乙酯(1.9 ml, 50 %內含物, 3.3 mmol)中之溶液且在環境溫度下攪拌混合物隔夜。將反應混合物再次升溫至55℃,添加(4S)-𠳭烷-4-胺鹽酸鹽((152 mg, 0.82 mmol)、N,N-二異丙基乙胺(0.5 ml, 2.87 mmol)且在移除加熱後,2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物於乙酸乙酯中之溶液(0.6 ml, 50 %內含物, 1.03 mmol)且在環境溫度下持續攪拌3.5 h。隨後添加水(80 ml) 且在60℃下攪拌混合物20 min。在減壓下移除THF並使混合物冷卻至RT。濾出沈澱物,用水洗滌且在真空中乾燥。
產量:748 mg (78% 理論值)
LC-MS (方法2):Rt
= 0.97 min; MS (ESIneg): m/z = 465 [M]-
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.351 (0.58), 1.644 (3.27), 1.670 (3.71), 1.686 (3.38), 1.713 (3.35), 1.755 (1.16), 1.988 (0.44), 2.060 (2.11), 2.070 (2.36), 2.084 (2.76), 2.229 (2.51), 2.240 (2.55), 2.246 (2.47), 2.257 (1.85), 2.377 (4.33), 2.401 (4.40), 2.632 (0.47), 3.296 (0.44), 3.393 (1.42), 3.440 (1.96), 3.461 (3.53), 3.495 (2.87), 3.519 (4.15), 3.541 (2.36), 3.598 (1.27), 3.697 (2.22), 3.988 (5.45), 4.000 (6.33), 4.011 (5.09), 4.212 (1.89), 4.229 (4.40), 4.247 (3.20), 4.290 (3.49), 4.297 (3.31), 4.303 (3.60), 5.299 (1.82), 5.310 (4.00), 5.325 (3.85), 5.336 (1.78), 6.793 (7.02), 6.810 (7.60), 6.933 (3.49), 6.948 (7.16), 6.963 (4.07), 7.168 (3.75), 7.184 (6.29), 7.199 (3.09), 7.414 (6.47), 7.429 (6.04), 7.577 (4.11), 7.593 (7.05), 7.609 (4.36), 8.185 (7.96), 8.200 (7.64), 8.465 (6.55), 8.482 (6.18), 8.856 (16.00), 9.192 (5.85), 9.208 (5.71).
中間物 7A
8-溴-7-氟-4-羥基喹啉-3-甲酸乙酯
在室溫下攪拌2-溴-3-氟苯胺(24.89 g,131 mmol)與乙氧基亞甲基丙二酸二乙酯(28.33 g,131 mmol,26 mL)之混合物持續16 h。在250℃下在真空(60毫巴)下持續攪拌6小時。使反應混合物冷卻至室溫。在回流乙酸乙酯(400 mL)中攪拌固體殘餘物。濾出沈澱物並用乙酸乙酯洗滌。在乙醇(400 mL)及甲醇(40 mL)之回流混合物中攪拌固體。濾出熱懸浮液。用乙醇洗滌固體並在空氣中乾燥。
產量:28.60 g (83 mmol, 63%理論值)
LC-MS (方法1):Rt
= 1.73 min, m/z = 314/316 (M+H)+ 1
H-NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.45 (s, 1H), 8.22 (m, 1H), 7.50 - 7.39 (m, 1H), 4.23 (d, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
中間物 8A
8-溴-4-氯-7-氟喹啉-3-甲酸乙酯
向攪拌氧氯化磷(38.4 g,250 mmol,23 ml)中添加8-溴-7-氟-4-羥基喹啉-3-甲酸乙酯(步驟1) (23.6 g,75 mmol)。在80℃下攪拌所得懸浮液1小時。使混合物冷卻至室溫且倒入至劇烈攪拌之冰水(100 mL)中。在室溫下使所得混合物靜置兩天。藉由過濾收集沈澱物,且用水洗滌直至濾液呈中性。用乙醚與二異丙基醚之混合物(1:1;1 L)濕磨固體。濾出固體。在25℃下在真空中濃縮濾過物。在殘餘物與甲苯共同蒸發之後,獲得21.3 g (64 mmol,85%理論值)標題化合物。
產量:21.3 g (64 mmol, 85%理論值)
LC-MS (方法1):Rt
= 2.18 min, m/z = 332/334 (M+H)+
中間物 9A
4,8-二溴-7-氟喹啉-3-甲酸乙酯
在0℃,向8-溴-7-氟-4-羥基喹啉-3-甲酸乙酯(實例3,步驟2) (60.0 g, 181.2 mmol)於乾燥二氯甲烷(1500 ml)中之攪拌溶液中分批添加DMF (6.0 ml, 催化量)繼之添加磷醯基溴化物(77.9 g, 271.8 mmol)並在0℃下持續攪拌至環境溫度保持5 h。將反應質量倒入至冰水中並用固體碳酸氫鈉中和至pH 7。將混合物攪拌30 min並分離有機相。用DCM萃取水相。在減壓下濃縮合併之有機相。藉由矽膠管柱層析(溶離劑:石油醚/乙酸乙酯,10:1)純化粗產物,得到53.32 g (77 %理論值)產物。
LC-MS (方法2):Rt
= 1.19 min; MS (ESIpos): m/z = 376 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.375 (7.47), 1.393 (16.00), 1.411 (7.67), 2.524 (0.74), 4.426 (2.42), 4.444 (7.47), 4.461 (7.34), 4.479 (2.33), 7.897 (1.80), 7.920 (2.69), 7.941 (2.06), 8.443 (1.83), 8.457 (1.91), 8.466 (1.82), 8.481 (1.75), 9.179 (4.99).
中間物 10A
8-溴-4-乙基-7-氟喹啉-3-甲酸乙酯
在氬氣下,向4,8-二溴-7-氟喹啉-3-甲酸乙酯(步驟1, 30.0 g, 79.6 mmol)於脫氣二噁烷(300ml)中之溶液中添加乙基酸(10.6 g, 143 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(4.22 g, 5.17 mmol)及氟化銫(26.0 g, 171 mmol)且在70℃浴溫下攪拌混合物隔夜。添加水及乙酸乙酯以溶解反應混合物且在降低的壓力下蒸發有機溶劑。用DCM萃取水相數次,乾燥並蒸發合併之有機相。藉由急驟層析法在二氧化矽上利用環己烷/乙酸乙酯(4-18%)以數份純化殘餘物(28g),得到純(17.56 g)及混合餾分(4.79 g)。在相同條件下層析混合餾分,得到純材料(1.44 g)及混合餾分(1.99 g)。藉由製備型HPLC (RP 18, 0.1%水性甲酸及乙腈之梯度)純化後者,得到更純的材料(1.33 g)。
總產量 20.33 g (78%理論值)
LC-MS (方法4):Rt
= 3.55 min; MS (ESIpos): m/z = 326 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.275 (4.81), 1.288 (10.56), 1.300 (4.53), 1.376 (7.45), 1.388 (16.00), 1.395 (0.68), 1.400 (7.58), 3.389 (1.35), 3.402 (4.01), 3.414 (3.89), 3.427 (1.17), 4.405 (2.31), 4.417 (7.12), 4.428 (7.00), 4.440 (2.15), 7.776 (1.85), 7.790 (2.36), 7.791 (2.28), 7.805 (1.87), 8.451 (1.74), 8.461 (1.80), 8.467 (1.72), 8.476 (1.60), 9.219 (7.16).
中間物 11A
8-溴-4-乙基-7-氟喹啉-3-甲酸
8-溴-4-乙基-7-氟喹啉-3-甲酸乙酯(19.0 g, 58.3 mmol)於乙醇(80 ml)及THF (80 ml)中之混合物係用氫氧化鈉水溶液(35 ml, 5.0 M, 175 mmol)逐滴處理並在80℃下攪拌30 min。在40℃下在攪拌下將反應混合物緩慢添加至水(200 ml)及甲酸(13.2 ml)中。為完成沈澱,大大地蒸發有機溶劑並添加氫氯酸(15 ml, 5.0 M) (pH 2)。用數份水洗滌濾出沈澱物,並在真空中乾燥。
產量:17.27 g (95%純度,95% 理論值)
LC-MS (方法2):Rt
= 0.87 min; MS (ESIpos): m/z = 298 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.267 (7.94), 1.279 (16.00), 1.291 (7.47), 1.447 (0.45), 3.447 (2.52), 3.459 (6.78), 3.472 (6.52), 3.484 (2.11), 7.759 (2.54), 7.774 (4.56), 7.788 (2.55), 8.439 (2.58), 8.449 (2.82), 8.454 (2.85), 8.464 (2.37), 9.244 (10.71), 13.665 (1.91).
中間物 12A
8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-乙基-7-氟喹啉-3-甲醯胺
將8-溴-4-乙基-7-氟喹啉-3-甲酸(17.3 g, 57.9 mmol)於THF (300 ml)中之懸浮液加熱至60℃並用(4S)-𠳭烷-4-胺鹽酸鹽(14.0 g, 75.3 mmol)、N,N-二異丙基乙胺(40 ml, 230 mmol)處理。在攪拌下逐滴添加2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物於乙酸乙酯中之溶液(55 ml, 50 %內含物, 93 mmol),暫時移除加熱以將溫度保持在60℃與65℃之間。在添加完成後,在60℃下攪拌混合物1 h。添加水(300 ml),在降低壓力下大大地移除THF且在60℃下攪拌混合物45 min。過濾沈澱物,用水洗滌且在50℃下在真空中乾燥。
產量:24.0 g (97 %理論值)
LC-MS (方法4):Rt
= 3.37 min; MS (ESIpos): m/z = 429 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.265 (7.90), 1.278 (16.00), 1.290 (7.22), 2.050 (1.41), 2.055 (1.44), 2.062 (1.53), 2.067 (1.48), 2.073 (1.72), 2.084 (0.99), 2.215 (1.72), 2.223 (1.65), 2.229 (1.65), 2.238 (1.21), 2.386 (0.41), 2.425 (0.80), 2.653 (0.58), 3.223 (2.36), 3.235 (6.25), 3.248 (6.02), 3.260 (2.17), 4.231 (1.22), 4.245 (2.98), 4.250 (2.22), 4.258 (2.47), 4.263 (2.12), 4.271 (2.13), 4.276 (2.43), 4.282 (2.20), 4.288 (2.44), 4.295 (1.01), 4.301 (1.01), 5.297 (1.25), 5.306 (2.53), 5.320 (2.44), 5.330 (1.08), 6.794 (4.46), 6.807 (4.69), 6.928 (2.32), 6.939 (4.56), 6.951 (2.53), 7.166 (2.29), 7.177 (3.74), 7.189 (1.85), 7.357 (4.02), 7.370 (3.65), 7.736 (3.06), 7.751 (4.60), 7.766 (3.06), 8.364 (2.91), 8.374 (3.11), 8.380 (3.01), 8.390 (2.77), 8.939 (12.93), 9.149 (3.67), 9.163 (3.55).
中間物 13A
8-溴-4-氯-7-氟喹啉-3-甲酸
在室溫下,用氫氧化鈉水溶液(14 mL 45%氫氧化鈉稀釋於0.8 mL水中)逐滴處理8-溴-4-氯-7-氟喹啉-3-甲酸乙酯(實例8A) (11.9 g, 35.7 mmol)於THF (82 ml)中之混合物,隨後用15 mL水稀釋。濾出出現的沈澱物並在攪拌下緩慢添加至水(200 mL, T = 40℃)中。在60℃下用甲酸(59 mL)處理所得混合物。將沈澱物濾出,用數份水洗滌並在空氣中乾燥。
產量:9.4 g (88%純度,76%理論值)
LC-MS (方法5):Rt
= 0.774 min; m/z = 305.9 (M+H)+ 1
H-NMR (400 MHz, DMSO-d
6) δ 14.14 (bs), 9.29 (s, 1H), 8.51 - 8.47 (dd, 1H), 7.93 - 7.88 (t, 1H).
中間物 14A
8-溴-4-氯-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-氟喹啉-3-甲醯胺
向8-溴-4-氯-7-氟喹啉-3-甲酸(8.56 g, 24.41 mmol)於無水甲苯(180 mL)中之懸浮液中添加3滴DMF。隨後,在10分鐘內逐滴添加亞硫醯二氯(4.35 g, 36.62 mmol)。在90℃下攪拌2 h後,混合物冷卻至室溫且在減壓下移除溶劑。將殘餘物溶解於無水四氫呋喃(200 mL)中且在添加(4S)-𠳭烷-4-胺鹽酸鹽(4.53 g, 24.41 mmol)及N,N-二異丙基乙胺(24.47 g, 189 mmol)後,在室溫下繼續攪拌18 h。在減壓下移除溶劑,並將殘餘物分配於水(150 mL)與二氯甲烷(150 mL)之間。將沈澱物濾出,用數份水洗滌並在空氣中乾燥。
產量:10.16 g (96%理論值)
LC-MS (方法5):Rt
= 1.26 min; m/z = 435 (M+H)+
logP (HCOOH) (方法0) = 3.181
H-NMR (400 MHz, DMSO-d
6) δ 9.30 - 9.28 (m, 1H), 9.08 (s, 1H), 8.43 - 8.39 (m, 1H), 7.92 - 7.88 (m, 1H), 7.40 - 7.38 (m, 1H), 7.21 - 7.16 (m, 1H), 6.96 - 6.92 (m, 1H), 6.82 - 6.79 (m, 1H), 5.29 (m, 1H), 4.30 - 4.21 (m, 2H), 2.25 - 2.20 (m, 1H), 2.11 - 2.07 (m, 1H).
中間物 15A
8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-氟-4-(3-氟氮雜環丁-1-基)喹啉-3-甲醯胺
在60℃下攪拌8-溴-4-氯-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基] -7-氟喹啉-3-甲醯胺(實例14A) (295 mg, 0.677 mmol)、3-氟氮雜環丁烷鹽酸鹽(155 mg, 1.39 mmol)及1,4-二氮雜雙環[2.2.2]辛烷(310 mg, 2.764 mmol)於四氫呋喃(10 mL)中之混合物18 h。使混合物冷卻至室溫,添加水並用二氯甲烷(3×10 mL)萃取水層。乾燥溶劑並在減壓下移除,留下297 mg (93%理論值)標題化合物。
LC-MS (方法5):Rt
= 0.67 min; m/z = 475.9 (M+H)+
logP (HCOOH) (方法 0) = 1.291
H-NMR (400 MHz, DMSO-d
6) δ 9.10 - 9.08 (m, 1H), 8.56 (s, 1H), 8.12 - 8.08 (m, 1H), 7.44 - 7.39 (m, 1H), 7.34 - 7.32 (m, 1H), 7.21 - 7.16 (m, 1H), 6.95 - 6.91 (m, 1H), 6.82 - 6.80 (m, 1H), 5.56 - 5.38 (m, 1H), 5.22 - 5.20 (m, 1H), 4.73 - 4.53 (m, 4H), 4.28 - 4.26 (m, 2H), 2.19 - 2.16 (m, 1H), 2.09 - 2.00 (m, 1H).
中間物 16A
8-溴-7-氟-4-[4-(甲氧基羰基)四氫-2H-哌喃-4-基]喹啉-3-甲酸乙酯
由8-溴-4-氯-7-氟喹啉-3-甲酸乙酯(實例8A)根據實例4A給定之程序製備標題化合物。
產量:82%理論值
LC-MS (方法4):Rt = 3.28 min; MS (ESIpos): m/z = 440 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.362 (4.09), 1.374 (8.34), 1.385 (4.08), 2.197 (0.71), 2.207 (0.89), 2.219 (1.15), 2.224 (1.09), 2.229 (1.08), 2.236 (0.93), 2.247 (0.82), 2.411 (2.32), 2.433 (1.85), 3.566 (16.00), 3.795 (0.53), 3.812 (2.47), 3.824 (2.83), 3.831 (4.67), 3.982 (0.61), 4.439 (1.34), 4.450 (3.95), 4.462 (3.85), 4.474 (1.23), 7.787 (1.17), 7.800 (1.50), 7.816 (1.22), 8.248 (1.21), 8.258 (1.28), 8.265 (1.21), 8.274 (1.11), 8.956 (4.93).
中間物 17A
8-溴-7-甲氧基-4-(四氫-2H-哌喃-4-基)喹啉-3-甲酸
在75℃浴溫下攪拌8-溴-7-氟-4-[4-(甲氧基羰基)四氫-2H-哌喃-4-基]喹啉-3-甲酸乙酯(中間物16A) (3.00 g, 6.81 mmol)、甲醇(15 ml)及氫氧化鈉水溶液(8.2 ml, 5 M, 41 mmol)隔夜。添加更多氫氧化鈉水溶液(2.7 ml, 5 M, 13.5 mmol)並回流混合物隔夜。添加水(30 mL)並用濃鹽酸將溫溶液酸化至pH 2。濾出沈澱物,用水洗滌且在真空中乾燥。
產量:2.3 g (96%純度,88%理論值)
LC-MS (方法4):Rt = 1.63 min; MS (ESIpos): m/z = 366 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.664 (2.08), 1.685 (2.17), 2.373 (0.64), 2.387 (1.49), 2.393 (1.56), 2.407 (1.48), 2.414 (1.41), 2.429 (0.74), 3.169 (0.43), 3.521 (1.42), 3.539 (2.67), 3.558 (1.51), 3.951 (0.63), 3.972 (1.14), 4.006 (2.13), 4.012 (2.27), 4.024 (2.09), 4.031 (1.96), 4.068 (16.00), 7.671 (2.40), 7.687 (2.47), 8.544 (2.28), 8.559 (2.17), 8.947 (3.71), 13.709 (0.47).
中間物 18A
8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-甲氧基-4-(四氫-2H-哌喃-4-基)喹啉-3-甲醯胺
向8-溴-7-甲氧基-4-(四氫-2H-哌喃-4-基)喹啉-3-甲酸(中間物17A) (300 mg, 0.82 mmol)於THF (5 ml)中之懸浮液中添加N,N-二異丙基乙胺(0.71 ml, 4.1 mmol)及HATU (289 mg, 1.02 mmol)並在室溫下攪拌溶液30 min。隨後添加(4S)-𠳭烷-4-胺鹽酸鹽(380 mg, 2.05 mmol)並且持續攪拌隔夜。在降低壓力下蒸發大部分THF,將殘餘物添加至水/乙醇(50 mL)之(2:1)混合物中且用乙酸酸化至pH 4.5。在50℃下攪拌混合物30 min,冷卻,過濾出沈澱物,用水/乙醇(2:1)洗滌且在真空中乾燥。
產量:311 mg (76%理論值)
LC-MS (方法4):Rt = 2.72 min; MS (ESIneg): m/z = 495 [M-H]-
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.638 (1.03), 1.675 (1.81), 1.711 (1.11), 2.054 (0.67), 2.081 (0.92), 2.219 (0.83), 2.232 (0.86), 2.240 (0.81), 2.378 (1.49), 2.409 (1.45), 3.436 (0.70), 3.464 (1.27), 3.492 (1.41), 3.519 (1.39), 3.547 (0.74), 3.692 (0.83), 3.992 (2.02), 4.005 (1.93), 4.019 (2.23), 4.050 (16.00), 4.216 (0.51), 4.236 (1.33), 4.257 (1.17), 4.282 (1.27), 4.297 (1.23), 5.300 (1.27), 5.320 (1.31), 6.787 (2.26), 6.807 (2.54), 6.925 (1.10), 6.943 (2.32), 6.962 (1.36), 7.161 (1.24), 7.180 (1.98), 7.199 (0.96), 7.403 (2.05), 7.421 (1.92), 7.636 (2.48), 7.660 (2.61), 8.463 (2.36), 8.487 (2.24), 8.781 (5.86), 9.114 (1.89), 9.135 (1.90).
實例 實例 1
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(3,6-二氫-2H-哌喃-4-基)-8- (2,3,5-三氟苯基)喹啉-3-甲醯胺
在氬氣下,向厚壁容器中饋入4-氯-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺(實例3A) (500 mg, 1.07 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼㖦-2-基)-3,6-二氫-2H-哌喃(246 mg, 1.17 mmol)、甲酸鉀(295 mg, 2.13 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(43.5 mg, 53 µmol)及脫氣的5:1之二噁烷/水混合物(4 ml)。容器經封蓋且在80℃下在攪拌下加熱隔夜。在矽藻土上過濾混合物並用乙酸乙酯洗滌。將濾過物用水稀釋並用乙酸乙酯萃取。乾燥且蒸發合併之有機相。藉由急驟層析在二氧化矽(50 g)上利用環己烷/乙酸乙酯(8-40%)純化殘餘物(650 mg)。
產量:500 mg (91%理論值)
LC-MS (方法2):Rt
= 1.14 min; MS (ESIpos): m/z = 517 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), 0.146 (0.54), 1.992 (1.11), 2.001 (1.30), 2.008 (1.31), 2.019 (1.65), 2.026 (1.38), 2.162 (1.42), 2.174 (1.44), 2.182 (1.34), 2.327 (0.54), 2.366 (0.64), 2.430 (2.29), 2.669 (0.53), 2.709 (0.50), 3.901 (1.68), 4.219 (2.74), 4.245 (4.37), 4.253 (4.09), 4.261 (3.62), 4.270 (3.71), 4.289 (1.96), 5.225 (0.89), 5.239 (2.03), 5.256 (2.03), 5.861 (2.53), 6.768 (4.46), 6.788 (4.87), 6.891 (2.01), 6.908 (4.36), 6.926 (2.57), 7.139 (2.23), 7.142 (2.32), 7.160 (3.78), 7.178 (1.85), 7.181 (1.79), 7.242 (1.88), 7.254 (1.90), 7.264 (1.94), 7.342 (3.24), 7.360 (3.01), 7.588 (0.68), 7.596 (0.82), 7.611 (1.51), 7.624 (1.54), 7.637 (1.54), 7.644 (0.96), 7.652 (0.83), 7.660 (0.76), 7.772 (2.74), 7.790 (4.75), 7.811 (4.54), 7.862 (5.09), 7.865 (5.41), 7.880 (3.55), 7.883 (3.29), 8.093 (4.73), 8.096 (4.68), 8.114 (4.19), 8.117 (3.89), 8.892 (16.00), 8.938 (3.57), 8.959 (3.47).
實例 2
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(四氫-2H-哌喃-4-基)-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
程序 1 :
在氬氣下,將N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(3,6-二氫-2H-哌喃-4-基)-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺(實例1) (500 mg, 0.97 mmol)溶解於乙酸乙酯/乙醇(2:1, 15 ml)中。添加催化劑10%鈀/木炭(125 mg),用氫氣替換氬氣,且在大氣壓力之氫氣下攪拌混合物18 h。反應混合物在矽藻土上過濾,用乙酸乙酯沖洗且在真空中濃縮。使殘餘物(560 mg,不同還原產物之粗混合物)溶解於DMSO (4.5 ml)中並用硝酸銨(2 M溶液於水中, 1.9 ml, 3.8 mmol)處理,產生淡褐色的懸浮液,在環境溫度下攪拌該懸浮液隔夜。藉由添加更多DMSO、乙腈及一些5 M甲酸使混合物溶解且經由製備型HPLC (C18, 梯度:0.1%甲酸/乙腈)直接地純化。產量:175 mg (31 %理論值)藉由急驟層析在二氧化矽上利用環己烷/乙酸乙酯(5-50%)再純化混合餾分(75 mg),產生第二產量37 mg (7%理論值)。
LC-MS (方法4):Rt
= 3.80 min; MS (ESIpos): m/z = 519 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.70), 0.008 (2.80), 1.687 (1.87), 1.724 (3.01), 1.763 (2.03), 2.030 (0.72), 2.038 (1.16), 2.045 (1.24), 2.057 (1.32), 2.073 (1.91), 2.080 (1.57), 2.088 (1.14), 2.192 (0.71), 2.201 (1.15), 2.214 (1.69), 2.226 (1.65), 2.235 (1.62), 2.248 (1.14), 2.256 (0.82), 2.269 (0.56), 2.395 (0.93), 2.425 (2.48), 2.454 (2.48), 2.523 (1.11), 3.457 (1.19), 3.486 (2.26), 3.515 (2.39), 3.545 (2.55), 3.572 (1.42), 3.730 (1.41), 4.000 (2.13), 4.010 (3.59), 4.024 (3.66), 4.038 (3.27), 4.204 (0.82), 4.211 (1.03), 4.232 (2.75), 4.239 (2.11), 4.252 (2.47), 4.262 (2.60), 4.273 (2.58), 4.280 (2.20), 4.289 (2.31), 4.301 (0.90), 4.308 (1.00), 4.317 (0.71), 5.286 (1.08), 5.301 (2.49), 5.320 (2.53), 5.335 (1.12), 6.778 (4.25), 6.781 (4.67), 6.799 (4.92), 6.801 (5.15), 6.910 (2.31), 6.913 (2.42), 6.929 (4.82), 6.931 (4.87), 6.947 (2.96), 6.950 (2.90), 7.150 (2.40), 7.154 (2.57), 7.171 (3.98), 7.189 (2.06), 7.193 (2.33), 7.204 (1.61), 7.208 (2.00), 7.220 (1.97), 7.230 (2.00), 7.242 (1.03), 7.398 (4.14), 7.416 (3.86), 7.571 (0.69), 7.578 (0.85), 7.586 (0.98), 7.593 (1.57), 7.598 (1.47), 7.606 (1.60), 7.614 (1.53), 7.620 (1.61), 7.627 (1.01), 7.634 (0.92), 7.642 (0.84), 7.774 (2.56), 7.792 (4.98), 7.813 (5.12), 7.832 (5.89), 7.835 (6.55), 7.850 (3.13), 7.853 (2.79), 8.561 (3.72), 8.564 (3.88), 8.582 (3.67), 8.585 (3.55), 8.738 (16.00), 9.160 (4.40), 9.180 (4.33).
程序 2 :
在氬氣下,向燒瓶中饋入8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(四氫-2H-哌喃-4-基)喹啉-3-甲醯胺(實例6A) (850 mg, 1.82 mmol)、2,3,5-三氟苯酸(160 mg, 0.91 mmol)、甲酸鉀(503 mg, 3.64 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(44.6 mg, 54.6 µmol)及(2'-胺基聯苯-2-基)(氯基)鈀-二環己基(2',4',6'-三異丙基聯苯-2-基)膦(1:1) (42.9 mg, 54.6 µmol)以及脫氣的5:1之二噁烷/水混合物(5.1 ml)。在70℃之經預加熱浴液中攪拌混合物持續45 min。隨後添加另一份2,3,5-三氟苯酸(160 mg, 0.91 mmol)並在相同溫度下攪拌45 min。再次重複後一製程。在消耗起始材料後,在室溫下攪拌添加水及乙酸乙酯,且分離各相。用乙酸乙酯萃取水相數次,在降低的壓力下乾燥且蒸發合併之有機相。藉由急驟層析在二氧化矽(100 g)上利用環己烷/乙酸乙酯(32-40%)純化殘餘物(1.15 g)。
產量:833 mg (88%理論值)
LC-MS (方法2):Rt
= 1.13 min; MS (ESIpos): m/z = 519 [M+H]+
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.691 (1.98), 1.716 (2.17), 1.736 (1.98), 1.761 (2.04), 2.038 (0.81), 2.045 (1.25), 2.050 (1.33), 2.060 (1.42), 2.073 (1.82), 2.078 (1.55), 2.085 (1.09), 2.200 (0.78), 2.207 (1.17), 2.217 (1.73), 2.227 (1.71), 2.234 (1.72), 2.245 (1.25), 2.252 (0.84), 2.262 (0.56), 2.405 (1.02), 2.429 (2.67), 2.453 (2.70), 3.464 (1.17), 3.485 (2.16), 3.508 (1.29), 3.523 (1.50), 3.544 (2.52), 3.567 (1.39), 3.730 (1.32), 4.003 (2.20), 4.013 (3.04), 4.025 (4.09), 4.036 (2.77), 4.046 (1.82), 4.212 (0.98), 4.218 (1.16), 4.234 (3.00), 4.240 (2.08), 4.251 (2.37), 4.257 (1.90), 4.268 (1.90), 4.275 (2.44), 4.281 (2.12), 4.288 (2.38), 4.298 (1.00), 4.304 (1.09), 4.310 (0.80), 5.292 (1.22), 5.304 (2.66), 5.320 (2.56), 5.331 (1.16), 5.752 (1.91), 6.783 (5.04), 6.798 (5.49), 6.915 (2.50), 6.930 (5.20), 6.945 (2.93), 7.154 (2.55), 7.157 (2.49), 7.171 (4.18), 7.185 (2.13), 7.188 (1.98), 7.208 (2.12), 7.217 (2.09), 7.225 (2.06), 7.399 (4.31), 7.415 (4.06), 7.574 (0.76), 7.580 (0.94), 7.586 (1.07), 7.592 (1.68), 7.602 (1.71), 7.609 (1.64), 7.613 (1.64), 7.619 (0.99), 7.624 (0.89), 7.631 (0.78), 7.778 (2.81), 7.793 (5.08), 7.810 (4.86), 7.833 (6.27), 7.835 (6.27), 7.847 (3.60), 8.563 (4.14), 8.580 (3.96), 8.738 (16.00), 9.159 (4.57), 9.176 (4.42).
實例 3
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-氟-4-(四氫-2H-哌喃-4-基)-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
標題化合物係以如針對實例4A、5A、6A及實例2,程序2所描述之方法類似的方式由8-溴-4-氯-7-氟喹啉-3-甲酸乙酯(實例8A)製備。
S (方法2):Rt
= 1.14 min; MS (ESIpos): m/z = 537 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.679 (4.00), 1.713 (6.39), 1.737 (3.34), 2.033 (2.47), 2.052 (2.85), 2.067 (3.55), 2.211 (2.97), 2.220 (3.09), 2.229 (2.93), 2.243 (2.14), 2.328 (0.95), 2.367 (2.64), 2.388 (4.62), 2.401 (5.48), 2.420 (5.36), 2.432 (5.24), 2.449 (2.76), 2.464 (2.06), 2.670 (0.95), 2.710 (0.91), 3.444 (1.32), 3.471 (3.63), 3.499 (4.04), 3.523 (3.09), 3.543 (4.29), 3.574 (2.23), 3.737 (3.01), 4.016 (7.26), 4.036 (6.06), 4.197 (2.06), 4.219 (4.21), 4.225 (4.91), 4.246 (4.41), 4.270 (4.74), 4.286 (4.16), 5.275 (2.27), 5.288 (5.07), 5.307 (5.11), 5.322 (2.19), 6.778 (9.73), 6.799 (10.85), 6.904 (4.87), 6.923 (10.35), 6.942 (6.10), 7.152 (5.03), 7.170 (8.37), 7.188 (4.00), 7.278 (3.96), 7.286 (4.00), 7.389 (8.87), 7.407 (8.29), 7.642 (1.57), 7.650 (1.90), 7.665 (3.42), 7.678 (3.34), 7.686 (3.34), 7.692 (3.38), 7.698 (2.10), 7.706 (1.86), 7.714 (1.73), 7.761 (5.44), 7.784 (10.27), 7.807 (5.61), 8.664 (5.11), 8.679 (5.65), 8.688 (5.53), 8.703 (4.95), 8.758 (15.75), 8.770 (16.00), 9.155 (6.72), 9.173 (6.47).
實例 4
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-乙基-7-氟-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
在氬氣下,向燒瓶中饋入8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯 -4-基]-4-乙基-7-氟喹啉-3-甲醯胺(實例12A) (13.0 g, 30.3 mmol)、2,3,5-三氟苯酸(2.67 g, 15.2 mmol)、甲酸鉀(8.37 g, 60.6 mmol)及(2'-胺基聯苯-2-基)(氯基)鈀-二環己基(2',4',6'-三異丙基聯苯-2-基)膦(1:1) (477 mg, 606 µmol)。添加脫氣的5:1之二噁烷/水混合物(140 ml)且在70℃下攪拌混合物45 min。在1.5 h內再添加兩部分之2,3,5-三氟苯酸(2.67 g, 15.2 mmol)並且在上次劑量後持續攪拌1.5 h。隨後,添加更多2,3,5-三氟苯酸(5.33 g, 30.3 mmol)及(2'-胺基聯苯-2-基)(氯基)鈀-二環己基(2',4',6'-三異丙基聯苯-2-基)膦(1:1) (238 mg, 303 µmol)並且在相同溫度下攪拌1 h。在RT下攪拌添加水及乙酸乙酯且分離各相。用乙酸乙酯萃取水相兩次,在降低的壓力下乾燥且蒸發合併之有機相。殘餘物(24 g)藉由急驟層析在二氧化矽上用DCM及甲醇(0-2%)純化且隨後在第二矽膠層析中利用環己烷-乙酸乙酯(10-25%)純化,產生7.63 g。剩餘混合餾份藉由製備型HPLC (RP 18,梯度:0.1%水性甲酸及乙腈)純化,得到更純的材料(0.75 g)。
總產量:8.38 g (58%理論值)
LC-MS (方法4):Rt
= 3.99 min; MS (ESIpos): m/z = 481 [M+H]+
¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.62), 1.305 (8.10), 1.317 (16.00), 1.318 (15.96), 1.329 (7.70), 1.397 (8.26), 2.020 (0.99), 2.026 (1.42), 2.031 (1.82), 2.037 (1.85), 2.042 (1.90), 2.049 (1.91), 2.054 (2.16), 2.060 (1.62), 2.065 (1.16), 2.181 (0.98), 2.187 (1.48), 2.195 (2.06), 2.203 (1.94), 2.209 (2.04), 2.218 (1.46), 2.223 (1.05), 2.232 (0.71), 2.516 (0.89), 2.520 (0.95), 2.523 (0.96), 3.227 (0.71), 3.236 (1.35), 3.249 (3.27), 3.257 (3.63), 3.261 (4.26), 3.270 (4.39), 3.282 (3.24), 3.294 (1.47), 3.304 (1.17), 4.214 (0.72), 4.219 (1.14), 4.226 (1.21), 4.233 (2.56), 4.239 (3.13), 4.245 (2.80), 4.252 (3.53), 4.255 (3.49), 4.261 (3.70), 4.266 (2.73), 4.272 (3.23), 4.280 (1.06), 4.285 (1.15), 4.291 (0.88), 5.280 (1.26), 5.291 (2.88), 5.301 (2.73), 5.312 (1.11), 6.781 (6.23), 6.783 (6.34), 6.795 (6.65), 6.796 (6.62), 6.907 (3.27), 6.919 (6.32), 6.932 (3.61), 7.153 (2.85), 7.164 (4.85), 7.176 (2.33), 7.295 (2.49), 7.302 (2.41), 7.334 (2.71), 7.345 (4.69), 7.356 (2.50), 7.660 (0.92), 7.665 (1.13), 7.670 (1.32), 7.675 (2.00), 7.678 (1.91), 7.683 (2.01), 7.689 (1.92), 7.692 (1.90), 7.697 (1.20), 7.702 (1.05), 7.707 (0.93), 7.780 (3.82), 7.795 (7.06), 7.811 (3.81), 8.484 (4.02), 8.494 (4.24), 8.500 (4.25), 8.510 (3.87), 8.812 (11.05), 8.818 (10.77), 9.124 (4.07), 9.137 (3.96).
實例 5
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-氟-4-(3-氟氮雜環丁-1-基)-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
在室溫下攪拌8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-氟-4-(3-氟氮雜環丁-1-基)喹啉-3-甲醯胺(實例15A) (1500 mg, 3.163 mmol)及雙(三苯膦)二氯鈀(II) (255 mg, 0.363 mmol)於1,4-二噁烷(50 mL)中之混合物2 h。在添加(2,3,5-三氟苯基)酸(2200 mg, 12.51 mmol)、碳酸鈉(5000 mg, 47.175 mmol)及水(6.20 mL)之後,在90℃下持續攪拌18 h。使混合物冷卻至室溫,添加水並且用二氯甲烷(3×100 mL)萃取水層。乾燥溶劑並在減壓下移除溶劑。藉由製備型HPLC (水/乙腈80:20 → 5:95)純化,獲得675 mg (40,6%理論值)標題化合物。
LC-MS (方法5):Rt
= 0.88 min; m/z = 526 (M+H)+
logP (HCOOH) (方法0) = 1.931
H-NMR (400 MHz, DMSO-d
6) δ 1.99 - 2.08 (m, 1H), 2.14 - 2.19 (m, 1H), 4.25 (t,J
= 3.5 Hz, 2H), 4.57 - 4.74 (m, 4H), 5.17 - 5.22 (m, 1H), 5.42 - 5.60 (m, 1H), 6.78 - 6.80 (m, 1H), 6.88 - 6.92 (m, 1H), 7.14 - 7.23 (m, 2H), 7.30 - 7.32 (m,1H), 7.44 - 7.49 (m, 1H), 7.55 - 7.65 (m, 1H), 8.20 - 8.24 (m, 1H), 8.43 (s, 1H), 9,03 - 9.06 (m, 1H).
實例 6
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-4-(3,6-二氫-2H-哌喃-4-基)-7-氟-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
已類似於實例1合成標題化合物。
LC-MS (方法2):Rt
= 1.15 min; MS (ESIpos): m/z = 535 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.66), 1.981 (2.08), 1.989 (2.69), 1.998 (2.43), 2.007 (2.94), 2.016 (2.83), 2.024 (2.32), 2.158 (2.87), 2.170 (2.86), 2.179 (2.72), 2.192 (1.96), 2.328 (0.57), 2.366 (1.31), 2.415 (3.83), 2.710 (0.44), 3.900 (3.04), 4.186 (2.08), 4.214 (5.03), 4.242 (7.22), 4.250 (7.35), 4.259 (6.65), 4.267 (6.99), 4.287 (3.94), 5.230 (3.88), 5.246 (3.82), 5.865 (5.17), 6.765 (8.88), 6.767 (9.12), 6.786 (10.18), 6.788 (10.05), 6.885 (4.24), 6.904 (9.03), 6.923 (5.30), 7.138 (4.63), 7.142 (4.76), 7.159 (7.78), 7.177 (3.82), 7.180 (3.67), 7.332 (8.89), 7.352 (6.35), 7.659 (1.33), 7.667 (1.60), 7.674 (1.88), 7.682 (3.03), 7.686 (2.92), 7.695 (3.04), 7.703 (3.02), 7.708 (3.04), 7.715 (1.97), 7.723 (1.71), 7.731 (1.56), 7.767 (6.31), 7.790 (12.55), 7.813 (6.93), 8.177 (6.63), 8.192 (7.10), 8.201 (6.80), 8.216 (6.23), 8.914 (15.39), 8.924 (16.00), 8.940 (6.05), 8.961 (5.60).
實例 7
N-[(4S)-3,4-二氫-2H-𠳭烯-4-基]-7-甲氧基-4-(四氫-2H-哌喃-4-基)-8-(2,3,5-三氟苯基)喹啉-3-甲醯胺
在氬氣下,向容器中饋入8-溴-N-[(4S)-3,4-二氫-2H-𠳭烯 -4-基]-7-甲氧基-4-(四氫-2H-哌喃-4-基)喹啉-3-甲醯胺(中間物18A),(200 mg, 0.4 mmol)、2,3,5-三氟苯酸(141 mg, 0.80 mmol)、氟化銫(182 mg, 1.21 mmol)、(2-二環己基膦-2',6'-二甲氧基聯苯基)[2-(2'-胺基 -1,1'-聯苯基)]甲磺酸鈀(II) (31.4 mg, 40.2 µmol)及脫氣的5:1之二噁烷/水混合物(2 ml),封蓋並且在60℃下攪拌隔夜。用甲酸水溶液(0.48 ml, 2.4 mmol)及DMSO處理混合物且藉由製備型HPLC (RP 18, 梯度:0.1%水性甲酸及乙腈)來純化。將產物懸浮於乙醇/水(3:1, 4 ml)中,攪拌隔夜,濾出,用乙醇/水(3:1)洗滌,且在真空中乾燥。
產量:138 mg (63%理論值)
LC-MS (方法2):Rt = 1.08 min; MS (ESIpos): m/z = 549 [M+H]+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.669 (0.85), 1.701 (1.34), 1.730 (0.71), 2.036 (0.61), 2.049 (0.74), 2.194 (0.69), 2.205 (0.66), 2.217 (0.67), 2.230 (0.47), 2.365 (0.50), 2.384 (0.44), 2.414 (1.11), 2.433 (1.06), 2.445 (1.10), 2.461 (0.67), 3.462 (0.75), 3.488 (0.82), 3.506 (0.71), 3.534 (1.04), 3.564 (0.54), 3.698 (0.67), 3.931 (16.00), 4.011 (1.49), 4.020 (1.56), 4.037 (1.35), 4.226 (1.03), 4.249 (1.41), 4.258 (1.28), 4.275 (0.99), 5.264 (0.50), 5.279 (1.10), 5.299 (1.12), 5.313 (0.51), 5.753 (0.81), 6.770 (1.91), 6.790 (2.17), 6.898 (1.05), 6.916 (2.21), 6.935 (1.29), 7.049 (0.79), 7.143 (1.04), 7.162 (1.77), 7.180 (0.85), 7.375 (1.84), 7.393 (1.72), 7.521 (0.68), 7.533 (0.71), 7.541 (0.70), 7.716 (2.41), 7.740 (2.55), 8.575 (2.30), 8.599 (2.15), 8.623 (3.23), 8.631 (3.13), 9.082 (1.39), 9.099 (1.37).表 1 :實例
O-Me代表甲氧基
O-iPr代表異丙氧基(isopropoxy/i-propoxy group)表 1a : 1 H-NMR 資料 表 2a-2e :中間物 表 2a 表 2b 表 2c 表 2d 表 2e 表 2f : 1 H-NMR 資料
實驗部分-生物分析 在所選生物分析中測試實例一或多次。當測試超過一次時,資料係以平均值形式抑或以中位值形式報導,其中
• 平均值(亦稱為算術平均值)表示所得值之總和除以所測試次數,且
• 中值表示當以升序或降序排列時該組值的中間值。若資料集中之值個數為奇數,則中值為中間值。若資料集中之值個數為偶數,則中位值為兩個中間值之算術平均值。
實例經合成一或多次。當合成超過一次時,根據生物分析之資料表示利用獲自一或多個合成批次之測試的資料集計算的平均值或中位值。
本發明化合物之活體外活性可在以下分析中展現:
活體外分析
1
:
秀麗隱桿線蟲
(C. elegans) Slo-1a-
對
重組秀麗隱桿線蟲細胞株之作用
產生穩定的秀麗隱桿線蟲
CHO
細胞株
CHO細胞株獲自ATCC,編碼ATCC CRL-9096。為用質體DNA轉染以表現秀麗隱桿線蟲Slo-1a (寄存編號AAL28102),將CHO細胞繼代至40%匯合,隨後將轉染溶液添加至細胞培養物中。轉染溶液包括300 μL OptiMEM (Life Technologies, Nr.: 31985)、2 μL (= 6 µg)含有秀麗隱桿線蟲Slo 1a基因之質體DNA及9 μL FugeneHD (Promega, Nr.: E2311),且添加至細胞中,之後在37℃、5% CO2
下培育48小時。將轉染培養基替換為含有額外G418 (2 mg/ml,Invitrogen, Nr.: 10131)之選擇培養基,且將細胞接種至384孔盤(300個細胞/孔)中。在幾週之後,用電壓敏感性染料(膜電位分析套組(Membrane Potential Assay Kit), Molecular Devices Nr.: R8034)測試剩餘存活細胞之K+通道表現。陽性細胞純系藉由有限稀釋技術來純化。為此,將電壓敏感性染料分析中具有最高且最強烈信號之純系進一步次選殖(培育)於384孔盤(0.7個細胞/孔)中,以獲得純系純度。由此產生表現秀麗隱桿線蟲Slo-1a之最終穩定的CHO細胞株。
細胞培養條件
細胞在37℃及5% CO2
下在具有Gutamax I (Invitrogen, Nr.: 32571)、補充有10% (v/v)熱不活化胎牛血清(Invitrogen, Nr.: 10500)、G418 (1 mg/ml,Invitrogen, Nr.: 10131)之MEMα中培養。使用阿庫酶(Accutase) (Sigma, Nr.: A6964)分離細胞。
薄膜電位量測
在384孔微量滴定盤(MTP, Greiner, Nr.: 781092)上執行實驗室化合物測試。將8000個細胞/孔接種於384孔MTP上且在37℃及5% CO2
下培養20至24小時。在移除細胞培養基之後,用台式液(tyrode) (150 mM NaCl、0.3 mM KCl、2 mM CaCl2
、1mM MgCl2
、0.8 mM NaH2
PO4
、5 mM葡萄糖、28 mM Hepes,pH 7.4)洗滌細胞一次,且接著在室溫下負載用台式液稀釋之薄膜電位分析套組之電壓敏感性染料1 h。
在開始使用FLIPR Tetra (Molecular Devices,激發510-545 nm,發射565-625 nm)螢光量測之後,添加測試化合物,之後添加KCl台氏液(最終分析濃度:70 mM KCl、2 mM CaCl2
、1 mM MgCl2
、0.8 mM NaH2
PO4
、5 mM葡萄糖、28 mM Hepes,pH 7.4,包括電壓敏感性染料)。7分鐘之後完成量測。
統計資料
藉由使用ActivityBase XLfit軟體(IDBS)評估資料以進行曲線擬合及計算半最大有效濃度(EC50
),且以負十進制對數(pE50
)報導。
對於以下實例,發現pE50
> 6.5 - 7.5:14。
對於以下實例,發現pE50
> 7.5 - 8.5:5、13。
對於以下實例,發現pE50
>8.5:1、2、4、7、10、11、12、15、16、19、21。
活體外分析
2
:
犬惡絲蟲
(D.immitis) Slo-1-
對於
重組犬惡絲蟲細胞株之作用
產生穩定的犬惡絲蟲
Slo -1CHO
細胞株
CHO細胞株獲自ATCC,編碼ATCC CRL-9096。為用質體DNA轉染以表現犬惡絲蟲Slo-1(基於蛋白質序列JQ730003,針對倉鼠最佳化之密碼子),將CHO細胞繼代至40%匯合,隨後將轉染溶液添加至細胞培養物中。轉染溶液包括300 μL OptiMEM (Life Technologies, Nr.: 31985)、2 μL (= 6 µg)含有犬惡絲蟲Slo-1基因之質體DNA及9 μL FugeneHD (Promega, Nr.: E2311),且添加至細胞中,之後在37℃、5% CO2
下培育48小時。將轉染培養基替換為含有額外G418 (2 mg/ml,Invitrogen, Nr.: 10131)之選擇培養基,且將細胞接種至384孔盤(300個細胞/孔)中。在幾週之後,用電壓敏感性染料(膜電位分析套組(Membrane Potential Assay Kit), Molecular Devices Nr.: R8034)測試剩餘存活細胞之K+通道表現。陽性細胞純系藉由有限稀釋技術來純化。為此,將電壓敏感性染料分析中具有最高且最強烈信號之純系進一步次選殖(培育)於384孔盤(0.7個細胞/孔)中,以獲得純系純度。由此產生表現犬惡絲蟲Slo 1之最終穩定的CHO細胞株。
細胞培養條件
細胞在37℃及5% CO2
下在具有Gutamax I (Invitrogen, Nr.: 32571)、補充有10% (v/v)熱不活化胎牛血清(Invitrogen, Nr.: 10500)、G418 (1 mg/ml,Invitrogen, Nr.: 10131)之MEMα中培養。使用阿庫酶(Accutase) (Sigma, Nr.: A6964)分離細胞。
薄膜電位量測
在384孔微量滴定盤(MTP, Greiner, Nr.: 781092)上執行實驗室化合物測試。將8000個細胞/孔接種於384孔MTP上且在37℃及5% CO2
下培養20至24小時。在移除細胞培養基之後,用台式液(tyrode) (150 mM NaCl、0.3 mM KCl、2 mM CaCl2
、1mM MgCl2
、0.8 mM NaH2
PO4
、5 mM葡萄糖、28 mM Hepes,pH 7.4)洗滌細胞一次,且接著在室溫下負載用台式液稀釋之薄膜電位分析套組之電壓敏感性染料1 h。
在開始使用FLIPR Tetra (Molecular Devices,激發510-545 nm,發射565-625 nm)螢光量測之後,添加測試化合物,之後添加KCl台氏液(最終分析濃度:70 mM KCl、2 mM CaCl2
、1 mM MgCl2
、0.8 mM NaH2
PO4
、5 mM葡萄糖、28 mM Hepes,pH 7.4,包括電壓敏感性染料)。7分鐘之後完成量測。
統計資料
藉由使用ActivityBase XLfit軟體(IDBS)評估資料以進行曲線擬合及計算半最大有效濃度(EC50
),且以負十進制對數(pE50
)報導。
對於以下實例,已發現pE50
>5.3-6.5:8、9、13、14、17、18、19。
對於以下實例,已發現pE50
>6.5-7.5:1、10、12、15、20。
對於以下實例,已發現pE50
>7.5-8.5:2、3、4、5、6、7、16、22。
活體外分析 3 : 巴西日圓線蟲 (Nippostrongylus brasiliensis , NIPOBR)
用含有100 U/ml青黴素、0.1 mg/ml鏈黴素及2.5 µg/ml兩性黴素B之鹽水緩衝液洗滌成年巴西日圓線蟲。將測試化合物溶解於DMSO中且使蠕蟲分別以最終濃度10 µg/ml (10 ppm)、1 µg/ml (1 ppm)在培養基中培育。使用培養基之等分試樣與陰性對照相比,以判定乙醯膽鹼酯酶活性。以讀數量測乙醯膽鹼酯酶之驅蠕蟲活性之原理描述於Rapson等人(1986)及Rapson等人(1987)中。
對於以下實例,在10 µg/ml下,活性(相較於陰性對照AChE之還原)高於80%:2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22。
對於以下實例,在1 µg/ml下,活性(相較於陰性對照AChE之還原)高於80%:1、2、3、4、5、6、7、9、10、11、12、15、16、17、18、19、20、21、22。
活體外分析 4 : 犬惡絲蟲微絲蟲 (Dirofilaria immitis
microfilariae , DIROIM L1)
將自血液新純化的≥250個犬惡絲蟲微絲蟲添加至含有營養物培養基及含測試化合物之DMSO的微量滴定盤之孔中。在濃度反應分析中一式兩份地測試化合物。使用暴露於DMSO且無測試化合物之幼蟲作為陰性對照。在與化合物一起培育72小時之後評估幼蟲。當與陰性對照相比運動性降低時判定功效。基於寬濃度範圍之評估,計算濃度反應曲線以及EC50
值。
對於以下實例,EC50 < 0.1 ppm:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22。
活體外分析 5 : 犬惡絲蟲 (DIROIM L4)
將自其載體(中間宿主)新分離之10個犬惡絲蟲第三階段幼蟲添加至含有營養物培養基及含測試化合物之DMSO的微量滴定盤之孔中。在濃度反應分析中一式兩份地測試化合物。使用暴露於DMSO且無測試化合物之幼蟲作為陰性對照。在與化合物一起培育72小時之後評估幼蟲。在此等72小時培育內,陰性對照中之大多數幼蟲蛻皮至第四階段幼蟲。當與陰性對照相比運動性降低時判定功效。基於寬濃度範圍之評估,計算濃度反應曲線以及EC50
值。
對於以下實例,EC50 < 0.1 ppm:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22。
活體外分析 6 : 短古柏線蟲 (Cooperia curticei) (COOPCU)
溶劑:二甲亞碸
為產生適合的活性化合物製劑,將10 mg活性化合物溶解於0.5 ml溶劑中,且用「林格氏溶液(Ringer's solution)」將濃縮物稀釋至所需濃度。
將大致40個線蟲幼蟲(短古柏線蟲)轉移至含有化合物溶液之測試管中。
在5天之後,記錄幼蟲死亡百分比。100%功效意謂所有幼蟲均被殺死;0%功效意謂無幼蟲被殺死。
在例如此測試中,以下來自製備實例之化合物在20 ppm之施用量下展示90%之良好活性:1。
在例如此測試中,以下來自製備實例之化合物在4 ppm之施用量下展示100%之良好活性:2。
在例如此測試中,以下來自製備實例之化合物在4 ppm之施用量下展示90%之良好活性:1。
在例如此測試中,以下來自製備實例之化合物在0.8 ppm之施用量下展示100%之良好活性:2。
在例如此測試中,以下來自製備實例之化合物在0.8 ppm之施用量下展示90%之良好活性:1。
活體外分析 7 : 撚轉血矛線蟲 ( Haemonchus contortus ) ( HAEMCO )
溶劑:二甲亞碸
為產生適合的活性化合物製劑,將10 mg活性化合物溶解於0.5 ml溶劑中,且用「林格氏溶液」將濃縮物稀釋至所需濃度。
將大致40個線蟲幼蟲(撚轉血矛線蟲)轉移至含有化合物溶液之測試管中。
在5天之後,記錄幼蟲死亡百分比。100%功效意謂所有幼蟲均被殺死,0%功效意謂無幼蟲被殺死。
在例如此測試中,以下來自製備實例之化合物在20 ppm之施用量下展示90%之良好活性:2。
在例如此測試中,以下來自製備實例之化合物在20 ppm之施用量下展示80%之良好活性:1。
在例如此測試中,以下來自製備實例之化合物在4 ppm之施用量下展示90%之良好活性:2。
調配實例
例示性調配物由含活性物質之10% Transcutol、10% Cremophor EL及80%等張性鹽水溶液組成。首先,將活性物質溶解於Transcutol中。在溶解於Transcutol中之後,添加Cremophor及等張性鹽水溶液。在以下活體內分析中使用此等調配物作為維護調配物。
本發明之調配物之實例為以下調配物實例F1。其中,將活性物質溶解於Transcutol中以形成儲備溶液A。接著,獲取0.100 mL此儲備溶液A且添加0.100 mL Cremophor EL及0.800 mL等張性鹽水溶液。所得液體調配物(調配物實例F1)之體積為1 mL。儲備溶液 A :
4.0 mg 實例2之化合物,
0.100 mL Transcutol。
調配物實例 F1 :
0.100 mL 儲備溶液A,
0.100 mL Cremophor EL,及
0.800 mL 等張性鹽水溶液。
活體內分析
撚轉血矛線蟲(Haemonchus contortus)/蛇形毛圓線蟲(Trichostrongylus colubriformis)/沙鼠
以實驗方式感染血矛線蟲及/或毛圓線蟲之沙鼠在晚期遺傳期間處理一次。測試化合物經調配呈溶液或懸浮液形式且經口或腹膜內施用。對於兩種施加使用相同的維護調配物。施用體積最大通常達至20 ml/kg。舉例而言,將40 g體重之沙鼠用調配物實例F1之0.200 mL調配物處理。此對應於用20 mg/kg體重處理。
當驗屍之後與經感染且經安慰劑處理之對照組中之蠕蟲計數相比,胃及小腸中之蠕蟲計數分別降低時,判定每群組之功效。
以下實例經測試且在既定處理下具有≥ 70%或更高的活性:
以下實例經測試且在既定處理下具有≥ 80%或更高的活性:
Claims (15)
- 一種通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,
- 如請求項1之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中: A 為A1或A2,
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:A 為A1或A2,
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:A 為A1或A2,
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:A 選自由以下組成之群:
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:R2 為四氫-2H-哌喃-4-基,Q 為2,3,5-三氟苯基。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:R2 為3,6-二氫-2H-哌喃-4-基,Q 為2,3,5-三氟苯基。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:R2 為乙基,R4 選自由以下組成之群:氫、鹵素、-OH、氰基、C1-C4烷基、C3-C6環烷基、具有1至5個鹵素原子之C1-C4鹵代烷基、C1-C4烷氧基-C1-C4烷基、C1-C4烷氧基、具有1至5個鹵素原子之C1-C4鹵代烷氧基、C1-C4烷基-C(O)-、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-S-C1-C4烷基、-S(O)-C1-C4烷基、-SO2-C1-C4烷基,較佳地氫、鹵素及C1-C4烷氧基,更 佳地氟、氯、甲氧基及異丙氧基,Q 為2,3,5-三氟苯基, 限制條件為當A為時,R4不為氫。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物,其中:R2 為3-氟氮雜環丁-1-基,Q 為2,3,5-三氟苯基。
- 一種製備如請求項1至10中任一項之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物的方法,該方法包含以下步驟:允許通式1N之中間化合物:
- 一種醫藥組合物,其包含如請求項1至10中任一項之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物及一或多種醫藥學上可接受之賦形劑。
- 一種如請求項1至10中任一項之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物之用途,其係用於製備用以控制、治療及/或預防疾病之藥物,其中該疾病為蠕蟲感染。
- 一種如請求項1至10中任一項之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物或鹽或彼等之混合物之用途,其係用於製備控制人類及/或動物之蠕蟲感染之藥物。
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CN112074514A (zh) | 2020-12-11 |
JP2021523131A (ja) | 2021-09-02 |
CA3099610A1 (en) | 2019-11-14 |
IL278472A (zh) | 2020-12-31 |
PL3790874T3 (pl) | 2023-06-19 |
ES2945559T3 (es) | 2023-07-04 |
BR112020022619A2 (pt) | 2021-02-02 |
AU2019266511B2 (en) | 2022-12-08 |
CO2020013876A2 (es) | 2020-11-20 |
TW202016100A (zh) | 2020-05-01 |
US20230141809A1 (en) | 2023-05-11 |
SG11202010024UA (en) | 2020-11-27 |
US11572357B2 (en) | 2023-02-07 |
IL278472B2 (en) | 2023-08-01 |
JP7403472B2 (ja) | 2023-12-22 |
CL2020002891A1 (es) | 2021-05-14 |
PT3790874T (pt) | 2023-05-31 |
DK3790874T3 (da) | 2023-05-15 |
EP3790874B1 (en) | 2023-03-15 |
UY38226A (es) | 2019-12-31 |
WO2019215182A1 (en) | 2019-11-14 |
PH12020551891A1 (en) | 2021-05-31 |
EP3790874A1 (en) | 2021-03-17 |
AU2019266511A1 (en) | 2020-10-22 |
US20210139468A1 (en) | 2021-05-13 |
KR20210006401A (ko) | 2021-01-18 |
MX2020011873A (es) | 2021-01-20 |
IL278472B1 (en) | 2023-04-01 |
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