WO2015172722A1 - 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
- Publication number
- WO2015172722A1 WO2015172722A1 PCT/CN2015/078918 CN2015078918W WO2015172722A1 WO 2015172722 A1 WO2015172722 A1 WO 2015172722A1 CN 2015078918 W CN2015078918 W CN 2015078918W WO 2015172722 A1 WO2015172722 A1 WO 2015172722A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- compound
- quinoline
- formula
- arh
- Prior art date
Links
- -1 6,8-disubstituted quinoline compound Chemical class 0.000 title claims abstract description 84
- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 103
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 29
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 206010039966 Senile dementia Diseases 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000004889 1-methylethylamino group Chemical group CC(C)N* 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 2
- 125000002704 decyl group Chemical group [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])* 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims 1
- 241000283690 Bos taurus Species 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-N iodic acid Chemical compound OI(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 229910021645 metal ion Inorganic materials 0.000 abstract description 17
- 102000012440 Acetylcholinesterase Human genes 0.000 abstract description 15
- 108010022752 Acetylcholinesterase Proteins 0.000 abstract description 15
- 229940022698 acetylcholinesterase Drugs 0.000 abstract description 15
- 230000009920 chelation Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
- 230000006933 amyloid-beta aggregation Effects 0.000 abstract description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000011161 development Methods 0.000 description 10
- 230000018109 developmental process Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000002776 aggregation Effects 0.000 description 9
- 238000004220 aggregation Methods 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 238000002211 ultraviolet spectrum Methods 0.000 description 8
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 7
- 229960004136 rivastigmine Drugs 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical group CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 6
- 229910052742 iron Inorganic materials 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000007131 anti Alzheimer effect Effects 0.000 description 5
- 210000004556 brain Anatomy 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
- 238000012360 testing method Methods 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- BKPWLUIJVRXJSS-UHFFFAOYSA-N 6-(1-chloroethyl)-8-methoxyquinoline Chemical compound ClC(C)C=1C=C2C=CC=NC2=C(C=1)OC BKPWLUIJVRXJSS-UHFFFAOYSA-N 0.000 description 4
- 0 COc1cc(C(*)=O)cc2cccnc12 Chemical compound COc1cc(C(*)=O)cc2cccnc12 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- VSDGOPZNQYZNJN-UHFFFAOYSA-N 6-(1-morpholin-4-ylethyl)quinolin-8-ol Chemical compound O1CCN(CC1)C(C)C=1C=C2C=CC=NC2=C(C=1)O VSDGOPZNQYZNJN-UHFFFAOYSA-N 0.000 description 3
- 229940124596 AChE inhibitor Drugs 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 3
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 229910001431 copper ion Inorganic materials 0.000 description 3
- 229960000958 deferoxamine Drugs 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- BBKXVTROSBMDPM-UHFFFAOYSA-N 4-[1-(8-methoxyquinolin-6-yl)ethyl]morpholine Chemical compound COC=1C=C(C=C2C=CC=NC=12)C(C)N1CCOCC1 BBKXVTROSBMDPM-UHFFFAOYSA-N 0.000 description 2
- HOOKRVMJOOSXHS-UHFFFAOYSA-N 6-(1-piperidin-1-ylethyl)quinolin-8-ol Chemical compound N1(CCCCC1)C(C)C=1C=C2C=CC=NC2=C(C=1)O HOOKRVMJOOSXHS-UHFFFAOYSA-N 0.000 description 2
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 2
- XZVYDRLPXWFRIS-UHFFFAOYSA-N n-ethyl-n-methylcarbamoyl chloride Chemical compound CCN(C)C(Cl)=O XZVYDRLPXWFRIS-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- XERCJEIOYAGGPV-NRYLJRBGSA-N (2R)-2-(methylamino)butanedioic acid Chemical compound CN[C@H](CC(O)=O)C(O)=O.CN[C@H](CC(O)=O)C(O)=O XERCJEIOYAGGPV-NRYLJRBGSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- QPEQGXYEOBHHGH-UHFFFAOYSA-N 1-(8-methoxyquinolin-6-yl)-N-methylethanamine Chemical compound COC=1C=C(C=C2C=CC=NC=12)C(C)NC QPEQGXYEOBHHGH-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DKDWUCSYHFXIII-UHFFFAOYSA-N 6-[1-(4-methylpiperazin-1-yl)ethyl]quinolin-8-ol Chemical compound CN1CCN(CC1)C(C)C=1C=C2C=CC=NC2=C(C=1)O DKDWUCSYHFXIII-UHFFFAOYSA-N 0.000 description 1
- HASNOEQUJCRVES-UHFFFAOYSA-N 8-methoxy-6-[1-(4-methylpiperazin-1-yl)ethyl]quinoline Chemical compound COC=1C=C(C=C2C=CC=NC=12)C(C)N1CCN(CC1)C HASNOEQUJCRVES-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- KZCQWZZPZFJTPF-HJWRWDBZSA-N CC/C(/NCC)=C(\C=C)/OC Chemical compound CC/C(/NCC)=C(\C=C)/OC KZCQWZZPZFJTPF-HJWRWDBZSA-N 0.000 description 1
- 102000017926 CHRM2 Human genes 0.000 description 1
- JXXVYYHNERBSBL-UHFFFAOYSA-N COc1cc(Br)cc2cccnc12 Chemical compound COc1cc(Br)cc2cccnc12 JXXVYYHNERBSBL-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 101150012960 Chrm2 gene Proteins 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LHXOCOHMBFOVJS-OAHLLOKOSA-N Ladostigil Chemical compound CCN(C)C(=O)OC1=CC=C2CC[C@@H](NCC#C)C2=C1 LHXOCOHMBFOVJS-OAHLLOKOSA-N 0.000 description 1
- GABNZWBMSKAYMV-UHFFFAOYSA-N N,N-diethyl-1-(8-methoxyquinolin-6-yl)ethanamine Chemical compound C(C)N(C(C)C=1C=C2C=CC=NC2=C(C=1)OC)CC GABNZWBMSKAYMV-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- SLGJWJHKPDNHLM-UHFFFAOYSA-N N-ethyl-1-(8-methoxyquinolin-6-yl)-N-methylethanamine Chemical compound CN(CC)C(C)C=1C=C2C=CC=NC2=C(C=1)OC SLGJWJHKPDNHLM-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005567 fluorenylene group Chemical group 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229950008812 ladostigil Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- PJLHXSBKGRJXHA-KTXUZGJCSA-N n-ethylcarbamoyl chloride Chemical group CCN[11C](Cl)=O PJLHXSBKGRJXHA-KTXUZGJCSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- NEOCJLWBSDEGCI-UHFFFAOYSA-N quinolin-2-yl carbamate Chemical compound C1=CC=CC2=NC(OC(=O)N)=CC=C21 NEOCJLWBSDEGCI-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical class NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/32—Esters
- C07D215/34—Carbamates
-
- 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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
Definitions
- the present invention relates to a derivative of quinoline, and in particular to a 6,8-disubstituted quinoline compound, a pharmaceutically acceptable salt, and a process for the preparation and use thereof.
- AD Alzheimer's disease
- the main drug is the Acetylcholinesterase (AChE) inhibitor and one N-methyl-D-aspartic acid (N-methyl-D-aspartic acid).
- AChE Acetylcholinesterase
- N-methyl-D-aspartic acid N-methyl-D-aspartic acid
- NMDA N-methyl-D-aspartic acid receptor antagonists
- the AChE inhibitor rivastigmine
- rivastigmine is currently the first-line drug for clinical use, with low toxicity, good pharmacokinetic properties, and no drug-interacting interactions.
- the present invention provides a novel and highly effective dual-target anti-AD compound 6,8-disubstituted quinoline compound and a pharmacy thereof, in view of the fact that the existing anti-AD drugs are single-target therapeutic drugs and can only delay the development of AD diseases. Acceptable salt.
- R4 or R 5 are independently selected from the group consisting of H, C r C 4 fluorenyl, dC 4 alkenyl, dC 4 halodecyl, C r C 4 oxadecyl, d-azaindenyl, aryl, anthracene group, an aryl group embankment group, halogenated aryl group, or, R 5 and N constituting five-, six- or seven-membered ring, a five-, six- or seven-membered ring is oxazolyl, pyrrolyl, Pyrrolidinyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, methylpiperazinyl, homopiperazinyl, morpholinyl or homopiperidinyl or a substituted thereof;
- R 3 is independently selected from the group consisting of d-dodecyl, d-doalkenyl, Ci-Cio decyl, C dooxalinyl, Ci-Cio azaindolyl; X is oxygen or sulfur.
- the compound having the structure of Formula I has a good inhibitory effect on acetylcholinesterase in vitro, and has significant metal ion chelation and ⁇ aggregation inhibition.
- R 2 is independently - R4R 5 , wherein R 5 is independently selected from H, methyl, ethyl, propyl, isopropyl, or R 4 , R 5 and N Forming a five-, six- or seven-membered ring, the five-, six-, or seven-membered ring is pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, homopiperazinyl, morpholinyl Or homopiperidinyl; R 3 is independently selected from methyl, ethyl, propyl, isopropyl, vinyl, allyl; X is oxygen or sulfur.
- R 5 is independently selected from H, methyl, ethyl, propyl, isopropyl, or R 5 and N constitute a five-, six- or seven-membered ring, said five-member,
- the six- or seven-membered ring is pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, homopiperazinyl, morpholinyl or homopiperidinyl;
- R 3 is independently selected from methyl, ethyl , propyl, isopropyl, vinyl, allyl.
- the 6,8-disubstituted quinoline compound is selected from the group consisting of:
- the pharmaceutically acceptable salt is a salt formed by reacting the 6,8-disubstituted quinoline compound with an inorganic acid or an organic acid.
- the pharmaceutically acceptable salt is hydrochloride, hydrogen oxalate, hydroiodide, sulphate, hydrogen sulphate, phosphate, acetate, propionate, butyrate, grass An acid salt, a tartrate salt, a methanesulfonate salt, a p-toluenesulfonate salt, a fumarate salt, a taurate salt, a citrate salt or a succinate salt.
- the invention also provides a preparation method of the 6,8-disubstituted quinoline compound, which has the advantages of wide source of raw materials, low cost, simple operation and mild conditions.
- a method for preparing a 6,8-disubstituted quinoline compound which comprises a 6,8-disubstituted quinoline compound II as a starting material, which is VI by nucleophilic, reduction, halogenation, and then with a halogenated hydrocarbon
- the nuclear substitution reaction introduces an R 2 group, which is demethylated under HBr conditions, and further reacted with an acid chloride to obtain a series of 6,8-disubstituted quinoline compound I. Specifically, the following steps are included:
- a compound of the formula II is reacted with a compound of the formula III in a first organic solvent to give a compound of the formula IV, the reaction temperature is from room temperature to reflux, and the reaction time is from 1 to 12 hours;
- a compound of the formula VI is reacted with a compound of the formula VII in a fourth organic solvent to give a compound of the formula VIII, the reaction temperature is from room temperature to reflux, and the reaction time is from 1 to 12 hours;
- a compound of the formula VIII is reacted with hydrogen desert acid to give a compound of the formula IX, the reaction temperature is from room temperature to 200 ° C, and the reaction time is 12 72 hours;
- a compound of the formula IX is reacted with a compound of the formula X in the presence of an acid-binding agent in a fifth organic solvent to give a compound of the formula I, the reaction temperature is -50 to 50 ° C, and the reaction time is 1 to 24 hours. ;
- R 3 is a fluorenyl group
- Re is a corresponding fluorenylene group.
- R 3 is CH 3 CH 2 -
- R 3 is an alkenyl group
- the first organic solvent used in the step (1) is selected from any one or a mixture of methanol, ethanol, and ethylene glycol.
- the first organic solvent in the step (1) is ethanol.
- the second organic solvent used in the step (2) is selected from any one or a mixture of tetrahydrofuran, diethyl ether, acetone, butanone; and the reducing agent is sodium borohydride or lithium aluminum hydride.
- the second organic solvent in the step (2) is tetrahydrofuran; and the reducing agent is sodium borohydride.
- the third organic solvent used in the step (3) is selected from any one or a mixture of acetonitrile, acetone, trichloromethane and chloroform.
- the third organic solvent in the step (3) is methylene chloride.
- the fourth organic solvent used in the step (4) is selected from any one or a mixture of acetonitrile, acetone, methyl ethyl ketone and methylene chloride.
- the fourth organic solvent in the step (4) is acetonitrile.
- the hydrogen desert acid concentration in the step (5) is any concentration of 10% to 48%.
- the hydrogen desert acid concentration in the step (5) is 40%.
- the fifth organic solvent in the step (6) is selected from any one or a mixture of tetrahydrofuran, acetone and dichloromethane, and the acid binding agent is selected from any one or a mixture of potassium (hydrogen)carbonate, sodium carbonate, butyl lithium and sodium hydride.
- the fifth organic solvent in the step (6) is tetrahydrofuran; the acid binding agent is sodium hydride.
- the pharmaceutically acceptable salt is prepared by the following steps, and the various 6,8-disubstituted quinoline compounds obtained by the reaction are dissolved in one of diethyl ether, acetone, methanol, ethanol and ethyl acetate, and added dropwise.
- a solution of an inorganic or organic acid is prepared as a pharmaceutically acceptable salt.
- the various 6,8-disubstituted quinoline compounds are dissolved in one of diethyl ether, acetone, methanol, ethanol or ethyl acetate, and an aqueous solution of ethyl acetate is added dropwise under ice water to prepare a hydrochloride.
- the intermediate compound of formula IV is:
- R 3 is methyl
- the intermediate compounds of formula V are:
- R 3 6-(1-Chloroethyl)-8-methoxyquinoline (ie, R 3 is methyl).
- the present invention also provides the 6,8-disubstituted quinoline compound and a pharmaceutically acceptable salt thereof for preparation and treatment Application in drugs for Alzheimer's disease. Preliminary pharmacological tests have found that most of these compounds have an inhibitory effect on acetylcholinesterase, some compounds have stronger inhibitory activity than the lead compound Rivastigmine, and all compounds have metal ion chelation ability.
- the invention adopts the AChE inhibitor rivastigmine as a lead compound, and introduces a series of 6,8-disubstituted quinoline compounds by introducing an 8-hydroxyquinoline fragment having a metal ion chelation on the basis of retaining the basic mother nucleus. It has the advantages of easy preparation of raw materials, simple operation, mild conditions, low cost and suitable for industrial production. DRAWINGS
- Figure 1 is a graph showing the ultraviolet spectrum of the hydrolysis product before and after the action of copper ions in Example 38;
- Figure 2 is a graph showing the ultraviolet spectrum of the hydrolysis product before and after the action of iron ions in Example 38;
- Figure 3 is a diagram showing the ⁇ aggregation state of the blank control in Example 39;
- Fig. 4 is a graph showing the aggregation state of ⁇ after the addition of the compound in Example 39. detailed description
- Example 1 7 6-(l-(Dimethylamino)ethyl)quinoline- 8 -yl-pyrrolosyl-1-carboxamide (I j)
- I j 6-(l-(Dimethylamino)ethyl)quinoline- 8 -yl-pyrrolosyl-1-carboxamide
- Example 14 substituting pyrrolidinyl-1-carbonyl chloride for N,N-dimethylcarbamoyl chloride.
- a brownish yellow oil Ij was obtained with a yield of 41%.
- Example 22 6-(l- (two Ethylamino)ethyl)quinoline-8-yl-methylformamide (I m)
- I m 6-(l- (two Ethylamino)ethyl)quinoline-8-yl-methylformamide
- Example 25 6-(1-(ethyl(methyl)amino)ethyl)hydroxyquinoline (IXd)
- Example 4 For the procedure, see Example 4, using pyrrole oxime instead of morpholine. A yellow oil was obtained, Vllle, yield 85%.
- Example 2 6-(1-(pyrrole-1-yl)ethyl) -8 -hydroxyquinoline (IXe) See Example 5 for the procedure. A yellow oily IXe was obtained with a yield of 45%.
- Example 31 6-(1-(piperidin-1-yl)ethyl) -8 -hydroxyquinoline (IXf)
- Example 34 (1- (4 - methylpiperazin-l-yl) ethyl) quinolinol (IXg)
- Example 35 6-(l- (4-Methylpiperazin-1-yl)ethyl)quinolin-8-yl-ethyl(methyl)carboxamide (Ir)
- Kg instead of Kb.
- the yellow oil I r was obtained in a yield of 40%.
- pCMV-AChE was transfected into HEK293 cells: pCMV-AChE plasmid was added to serum-free medium, and lipofectamineTM 2000 transfection reagent was added and mixed to prepare transfection solution, which was allowed to stand for 20 min.
- the cultured HEK293 cells were taken out, serum-free medium was added, and the transfection solution was slowly added dropwise, placed at 37 ° C, 5% CO 2 incubator for 1 h, discarded the culture solution, added complete medium, and cultured in an incubator. After 72 hours, the culture solution was collected, centrifuged at 12,000 rcf for 5 min, and the supernatant was taken as an enzyme solution, and the enzyme activity was immediately analyzed. The excess enzyme solution was stored in a refrigerator at -80 °C.
- Acetylcholinesterase inhibitory activity test Add 4 ⁇ l of enzyme solution, 20 ⁇ inhibitor (Ia ⁇ Ir ), 50 L DTNB ( 0.1% ), add water to 150 ⁇ , incubate at 37 °C for 5 min, add 50 LATCh (0.5 mmol) /L) Incubate at 37 °C for 15 min, stop the reaction by adding 50 ⁇ SDS (3%), and measure the OD value at 412 nm in triplicate.
- the enzyme inhibition rate was determined by selecting seven to nine concentrations of the compound according to the preliminary screening results, and the IC50 value was obtained by linear regression (software calculation) with the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate.
- Metal ion chelation ability test of hydrolysate The hydrolyzate was dissolved in 1 mL of methanol, and different concentrations of copper or iron ions were added, and the volume was adjusted to 100 mL with water, and the UV absorption at 200-600 nm was measured after 0.5 h. The ultraviolet spectrum of the hydrolyzate was also examined. The UV image of the hydrolyzate under different concentrations of metal ions is compared with the UV spectrum of the compound to determine whether it has metal ion chelation ability.
- the results of the compound II are as follows: In Fig.
- the curve a is the ultraviolet spectrum of the hydrolyzed product
- the curve b is the ultraviolet spectrum of the hydrolyzed product after the addition of the copper ion, and it can be clearly found in the figure: 1) the maximum absorption wavelength is shifted; 2) The absorption intensity at the maximum absorption wavelength of 240 nm of the hydrolyzed product changes significantly. It is indicated that the hydrolyzed product sequesters copper ions and forms a complex with it.
- curve a is the ultraviolet spectrum of the hydrolyzed product
- curve b is the ultraviolet spectrum of the hydrolyzed product after the addition of iron ions, which also shows that the hydrolyzate can chelate iron ions.
- Example 39 ⁇ aggregation inhibition ability test
- the ⁇ peptide was formulated into a 0.1 mM solution with 1% aqueous ammonia, and 50 ⁇ was added to a 50 ⁇ aqueous solution of metal ions (0.1 mM). After shaking at room temperature for 2 minutes, a solution of ⁇ Compound II (O.lmM) was added, 37 Shake for 48 hours at °C. The aggregation state of ⁇ was analyzed using a transmission electron microscope.
- Fig. 3 shows the ⁇ aggregation state of the blank control
- Fig. 4 shows the aggregation state of ⁇ after the addition of the compound. It can be clearly seen from the figure that the black plaque is reduced after the addition of the compound, indicating that the compound can inhibit the aggregation of ⁇ .
- these new compounds not only have acetylcholinesterase inhibitory activity and ⁇ aggregation inhibition ability, but also hydrolysate products with metal ion chelation, which can treat senile dementia from multiple targets, and have better anti-senile dementia application.
- the prospects have good business value.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种具有如式I所示结构的6,8-双取代喹啉化合物、其药学上可接受的盐、制备方法及其在治疗老年痴呆疾病方面的应用,该化合物具有乙酰胆碱酯酶抑制活性和Aβ聚集抑制能力,其水解产物具有金属离子螯合作用。
Description
说 明 书
6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 技术领域
本发明涉及一种喹啉的衍生物, 具体涉及一种 6,8-双取代喹啉化合物、 药学上可 接受的盐及制备方法和应用。 背景技术
目前我国人口的老龄化问题日趋严重, 《2011年度中国老龄事业发展统计公报》 显示, 截止 2011年末, 全国 60岁及以上人口数量已达 1.85亿, 已经进入了老年型社 会。 其中, 老年痴呆症等退行性疾病是老年人的常见病和多发病, 其发病率 65岁以上 为 8 % , 75岁以上为 20 % , 到 85岁以上则高达 40 %左右。
目前老年痴呆的治疗尚无特效药物, 主要的上巿药物为五个乙酰胆碱酯酶 (Acetylcholinesterase , AChE)抑制剂和一个 N-甲基 -D-天冬氨酸 (N-methyl-D-aspartic acid, NMDA)受体拮抗剂。 但其仅能延缓轻、 中度 AD病人的症状, 难以遏制或逆转 AD的病情发展。 研究表明, AD的发病机制十分复杂, 所以使用单一靶点药物不能有 效控制或治愈。 近年来, 双靶点药物治疗为 AD的新药研发提供了新的思路。 由于双 靶点药物通过对疾病的不同病理生理环节发挥作用, 可以增强疗效, 减少副作用。
近年来, 多靶点抗 AD药物的研发已经取得了一定的成果, 已经有多靶点药物进入 了临床试验。 比如进入临床 II期研究的 Ladostigil就具有 AChE和 MAO双重抑制活性。还 有部分化合物也处于临床前研究阶段。如 Kogen研究小组利用选择性 5-羟色胺再摄取抑 制剂(SSRI)氟西汀 (fluoxetine)和 AChE抑制剂利伐司替明中共有的甲乙胺结构进行骈 合, 得到新化合物 1对 AChE和 SERT都有较高的抑制活性; Elsinghorst等人通过含酰肼 的连接链将三碘季铵酚与他克林连接, 得到化合物 2具有拮抗 M2受体的能力, 并且对 AChE的抑制活性在纳摩尔水平。 (中国药物化学杂志.2011,21 :433-441. )
因此, 开发双靶点抗 AD药物的研究对我国医药产业和社会发展具有重大意义。 最近研究表明, 脑内金属离子的代谢絮乱可以加速 AD病情的发展, 特别是铁, 铜, 锌等离子。 通过对 AD病人脑内的金属离子浓度监测发现, AD患者脑内的金属 离子(铁, 铜, 锌)是正常人浓度的 3-7倍。 金属离子浓度异常不仅可以直接影响 AD 病程的发展, 还可以加速 Αβ的聚集, 促进 AD患者脑内的老年斑的形成。 因此, 金 属离子螯合剂亦是 AD治疗药物的热点研究领域之一。 去铁胺(DFO )是临床长期使 用的金属离子螯合剂, 为期两年的双盲实验表明, 肌注 DFO能够显著改善 AD患者的 症状。 氯碘羟喹(CQ )起初用于治疗疟疾, 后发现其具优良的金属离子螯合作用, II 期临床研究也表明氯碘羟喹可以明显减少患者脑内的淀粉样蛋白的聚集, 是一有前景 的 AD治疗药物。
AChE 抑制剂利伐斯替名是目前临床使用的一线药物, 具有低毒性, 良好的药代 动力学性质, 无药物间的相互作用等优势。
因此, 以 CQ和利伐斯替名为先导物, 开发具有双靶点, 多种抗 AD活性的化合 物具有良好的成药前景。 发明内容
针对已有的抗 AD药物都是单靶点治疗药物, 仅能延缓 AD疾病的发展, 本发明 提供一种新型、 高效的双靶点抗 AD化合物 6,8-双取代喹啉化合物及其药学上可接受 的盐。
R4或 R5独立地选自 H、 CrC4垸基、 d-C4烯基、 d-C4卤代垸基、 CrC4氧杂垸基、 d- 氮杂垸基、 芳基、 垸芳基、 垸氧基芳基、 卤代芳基, 或 、 R5与 N构成五元、 六元或七元环, 所述的五元、 六元或七元环为恶唑基、 吡咯基、 吡咯垸基、 咪唑基、 吡唑基、 哌啶基、 哌嗪基、 甲基哌嗪基、 高哌嗪基、 吗啉基或高哌啶基或其取代物;
R3独立地选自 d-do垸基、 d-do烯基、 Ci-Cio 代垸基、 C do氧杂垸基、 Ci-Cio 氮杂垸基; X为氧或硫。
具有式 I所示结构的化合物对乙酰胆碱酯酶有较好的体外抑制作用, 且具有显著 的金属离子螯合作用和 Αβ聚集抑制作用。
作为优选, 所述的 Ri、 R2的结构式独立地为 - R4R5, 其中 、 R5 独立地选自 H、 甲基、 乙基、 丙基、 异丙基, 或 R4、 R5与 N构成五元、 六元或七元环, 所述的五元、 六元或七元环为吡咯垸基、 哌啶基、 哌嗪基、 甲基哌嗪基、 高哌嗪基、 吗啉基或高哌 啶基; R3独立地选自甲基、 乙基、 丙基、 异丙基、 乙烯基、 烯丙基; X为氧或硫。
作为优选, 所述 、 R5 独立地选自 H、 甲基、 乙基、 丙基、 异丙基, 或 、 R5 与 N构成五元、 六元或七元环, 所述的五元、 六元或七元环为吡咯垸基、 哌啶基、 哌 嗪基、 甲基哌嗪基、 高哌嗪基、 吗啉基或高哌啶基; R3独立地选自甲基、 乙基、 丙基、 异丙基、 乙烯基、 烯丙基。
进一步优选, 所述的 6,8 -双取代喹啉化合物选自:
6-[ (1-甲基氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[ (1-甲基氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[ (1-甲基氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[ (1-甲基氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[ (1-甲基氨基)乙基] -8- { 1-[(1'-吗啉)甲酰基]氧基 }喹啉
6-[ (1-二甲氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[ (1-二甲氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[ (1-二甲氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[ (1-二甲氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[ (1-二甲氨基)乙基] -8- { 1-[(1'-吗啉)甲酰基]氧基 }喹啉
6-[ (1-甲乙氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[ (1-甲乙氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(l-甲乙氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(1-甲乙氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-甲乙氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉 6-[(1-二乙氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉 6-[1-(Γ-吗啉)乙基] -8-甲氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-二甲氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-二乙氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉 6^-0 '-吡 嫁)乙基 ]-8-甲氨基甲酰氧基喹啉
S- -G '-P比 嫁)乙基] -8-二甲氨基甲酰氧基喹啉
5- -G '-P比 嫁)乙基] -8-甲乙氨基甲酰氧基喹啉
6^-0 ' 比 嫁)乙基] -8-二乙氨基甲酰氧基喹啉
6^—0 '-吡咯浣)乙基]—8—{1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6- [1-(Γ-哌啶)乙基] 甲氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 二甲氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 甲乙氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 二乙氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉 6-[1-(4'-甲基哌嗪)乙基] -8-甲氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-二甲氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-二乙氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉 6-[(1-二甲氨基)乙基]— 8-{ 1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉 6-[(1-二甲氨基)乙基] - 8-{1-[(Γ-哌啶)甲酰基]氧基 }喹啉 6-[(1-甲乙氨基)乙基] - 8-{1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉 6-[(1-甲乙氨基)乙基] - 8-{1-[(Γ-哌啶)甲酰基]氧基 }喹啉 6-[(1-二乙氨基)乙基] - 8-{1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉 6-[(1-二乙氨基)乙基] - 8-{1-[(Γ-哌啶)甲酰基]氧基 }喹啉。 更进一步的优选, 所述的 6,8-双取代喹啉化合物选自:
If Ih II
所述的药学上可接受的盐为所述的 6,8-双取代喹啉化合物与无机酸、 有机酸反应 所形成的盐。 作为优选, 所述的药学上可接受的盐为盐酸盐、 氢漠酸盐、 氢碘酸盐、 硫酸盐、 硫酸氢盐、 磷酸盐、 乙酸盐、 丙酸盐、 丁酸盐、 草酸盐、 酒石酸盐、 甲磺酸 盐、 对甲苯磺酸盐、 富马酸盐、 牛磺酸盐、 柠檬酸盐或琥珀酸盐。
本发明还提供一种所述的 6,8-双取代喹啉化合物的制备方法, 具有原材料来源广 泛、 成本低、 方法操作简单、 条件温和等优点。
一种 6,8-双取代喹啉化合物的制备方法,以 6,8-双取代喹啉化合物 II为起始原料, 通过亲核、 还原、 卤代得到 VI , 再与与卤代烃的亲核取代反应引入 R2基团, 再在 HBr 条件下脱甲基,进一步与酰氯反应得到一系列的 6,8-双取代喹啉化合物 I。 具体包括以 下步骤:
(1)如式 II的化合物与如式 III的化合物在第一有机溶剂中反应得到如式 IV的化合 物, 反应温度为室温至回流, 反应时间为 1~12小时;
(2)如式 IV的化合物与还原剂在第二有机溶剂中反应得到如式 V的化合物, 反应温 度为 -20~40°C , 反应时间 12~72小时;
(3)如式 V的化合物在第三有机溶剂中, 与二氯亚砜反应得到如式 VI的化合物, 反 应温度为室温 ~150°C , 反应时间 1~24小时;
(4)如式 VI的化合物与如式 VII的化合物在第四有机溶剂中反应得到如式 VIII的化合 物, 反应温度为室温至回流, 反应时间 1~12小时;
(5)如式 VIII的化合物与氢漠酸反应得到如式 IX的化合物,反应温度为室温至 200°C , 反应时间 12 72小时;
(6)如式 IX的化合物在第五有机溶剂中,在缚酸剂的存在下与式 X化合物反应得到 如式 I的化合物, 反应温度为 -50~50°C , 反应时间 1~24小时;
反应式如下:
其中, Ri、 R2、 R3和 X的定义如前文所述; R6通过步骤(1 ) 的反应转化为 R3。 Re的具体结构可以根据本领域的技术人员根据现有知识确定, 当 R3为垸基的时候, Re为相应的亚垸基, 例如, 当 R3为 CH3CH2-的时候, Re为 CH3CH=; 当 R3为烯基的 时候, Re为相应的亚烯基, 例如, 当 为 CH2=CH-的时候, Re为 CH2=C=。
化合物 ΙΠ、 VII、 X为巿售商品, 化合物 II可根据美国专利 US20130116430公开的 方法制得。
步骤 (1)中所用的第一有机溶剂选用甲醇、 乙醇、 乙二醇中任一种或混合物。 作为 优选, 所述步骤 (1)中的第一有机溶剂为乙醇。
所述步骤 (2)中所用的第二有机溶剂选用四氢呋喃、 乙醚、 丙酮、 丁酮中任一种或 混合物; 还原剂为硼氢化纳或氢化锂铝。
作为优选, 所述步骤 (2)中的第二有机溶剂为四氢呋喃; 还原剂为硼氢化纳。
步骤 (3)中所用的第三有机溶剂选用乙腈、 丙酮、 三氯甲垸、 二氯甲垸中任一种或 混合物。 作为优选, 所述步骤 (3)中的第三有机溶剂为二氯甲垸。
步骤 (4)中所用的第四有机溶剂选用乙腈、 丙酮、 丁酮、 二氯甲垸中任一种或混合 物。 作为优选, 所述步骤 (4)中的第四有机溶剂为乙腈。
步骤 (5)中的氢漠酸浓度为 10%-48%的任意浓度。作为优选,所述步骤 (5)中的氢漠 酸浓度为 40%。
步骤 (6)中第五有机溶剂选用四氢呋喃、 丙酮、 二氯甲垸中任一种或混合物, 缚酸 剂选用碳酸(氢)钾、 碳酸纳、 丁基锂、 氢化纳中任一种或混合物。 作为优选, 所述 步骤 (6)中的第五有机溶剂为四氢呋喃; 缚酸剂为氢化纳。
所述的药学上可接受的盐的制备方法如下, 将反应制得的各种 6,8-双取代喹啉化 合物溶于乙醚、 丙酮、 甲醇、 乙醇、 乙酸乙酯中的一种, 滴加无机酸或有机酸的溶液, 制成药学上可接受的盐。
具体是将各种 6,8-双取代喹啉化合物溶于乙醚、 丙酮、 甲醇、 乙醇或乙酸乙酯中 的一种,于冰水洛下滴加盐酸乙酸乙酯溶液,制成盐酸盐;或将各种 Ν-取代芳基吡啶酮 化合物溶于乙醚、 丙酮、 甲醇、 乙醇或乙酸乙酯中的一种, 滴加等摩尔甲磺酸, 得其
甲磺酸盐; 或将各种 6,8-双取代喹啉化合物溶于乙醚、 丙酮、 甲醇、 乙醇或乙酸乙酯 中的一种, 于冰水浴下滴加浓硫酸溶液制成硫酸盐, 等等。
式 IV~IX中 Rt〜R3的定义如前文所述。
更优选地, 式 IV所示的中间体化合物为:
1-(8-甲氧基喹啉 -6-基)乙酮 (即 R3为甲基)。
式 V所示的中间体化合物为:
1-(8-甲氧基喹啉 -6-基)乙醇 (即 R3为甲基)。
式 VI所示的中间体化合物为:
6-(1-氯乙基 )-8-甲氧基喹啉(即 R3为甲基)。
式 VIII所示的中间体化合物为:
1-(8-甲氧基喹啉 -6-基) -N-甲基乙胺(即 R2为甲氨基, R3为甲基);
(8-甲氧基喹琳 -6—基) -N,N-二甲基乙胺(即 R2为二甲胺基, R3为甲基);
N-乙基 -1—(8-甲氧基喹啉—6-基) -N-甲基乙胺(即 R2为甲乙胺基, R3为甲基);
Ν,Ν-二乙基 -1-(8-甲氧基喹啉 -6-基)乙胺(即 R2为二乙胺基, R3为甲基);
8-甲氧基 -6-[1- (吡咯烷 -1-基)乙基]喹啉(即 R2为吡咯垸基, R3为甲基);
8-甲氧基 -6-[1- (哌啶 -1-基)乙基]喹啉 (即 R2为哌啶基, R3为甲基 );
4-[1—(8-甲氧基喹啉 -6-基)乙基]吗啉(即 R2为吗啉基, R3为甲基); 或
8-甲氧基 -6-[1-(4-甲基哌嗪 -1-基)乙基]喹啉 (即 R2为 N-甲基哌嗪基, R3为甲基)。 式 IX所示的中间体化合物为:
6-[1- (甲基胺)乙基]喹啉 -8-醇 (即 R2为甲氨基, R3为甲基);
6-[1- (二甲基胺)乙基]喹啉 -8-醇 (即 R2为二甲胺基, R3为甲基);
6-{ 1- [乙基 (甲基)胺]乙基 }喹啉 -8-醇 (即 R2为甲乙胺基, R3为甲基);
6-[1- (二乙基胺)乙基]喹啉 -8-醇 (即 R2为二乙胺基, R3为甲基);
6—[1- (吡咯垸 -1-基)乙基]喹啉 醇 (即 R2为吡咯垸基, R3为甲基);
6—[1- (哌啶 -1-基)乙基]喹啉―8—醇 (即 R2为哌啶基, R3为甲基 );
6- (1-吗啉乙基)喹啉 -8-醇 (即 R2为吗啉基, R3为甲基); 或
6一[1— (4-甲基哌嗪 -1-基)乙基]喹啉 -8-醇 (即 R2为 N-甲基哌嗪基, R3为甲基)。 本发明还提供了所述的 6,8-双取代喹啉化合物及其药学上可接受的盐在制备治疗
老年痴呆疾病药物中的应用。 初步的药理试验发现该类化合物大多数对乙酰胆碱酯酶 有抑制作用, 部分化合物其抑制活性强于先导化合物 Rivastigmine, 且所有化合物均 具有金属离子螯合能力。
本发明是以 AChE抑制剂 rivastigmine为先导化合物, 在保留基本母核基础上, 引 入具有金属离子螯合作用的 8-羟基喹啉片段得到一系列的 6,8-双取代喹啉化合物。 具 有原材料易于制备, 方法操作简单、 条件温和, 成本低, 适于工业化生产等优点。 附图说明
图 1为实施例 38中水解产物与铜离子作用前后的紫外光谱图;
图 2为实施例 38中水解产物与铁离子作用前后的紫外光谱图;
图 3为实施例 39中的空白对照的 Αβ聚集状态图;
图 4为实施例 39中加入化合物后 Αβ的聚集状态图。 具体实施方式
以下实施例用于说明本发明, 但不用来限制本发明的范围。
实施例 1、 1-(8-甲氧基喹啉-6-基)乙酮(^&)
将式 II 化合物 2.4g(10mmol)、 醋酸钯 110mg(0.5mmol)、 1,3-双 (二苯基膦)丙垸 410mg(lmmol)溶解于乙醇 20ml中, 氮气保护, 加入三乙胺 25mmol和 1- (乙烯基氧基) 丁垸 Ilia 30mmol , 加热至 150°C反应 24小时。 加水 30ml , 二氯甲垸 30 ml*3提取, 合并有机层, 干燥, 浓缩。 用硅胶柱分离 (石油醚: 乙酸乙酯: 三乙胺 =2: 1 : 0.1), 得 淡黄色固体 IVa, 收率 52%。 m.p. 64-66°C。
1H- MR (δ, CDC13): 9.03 (d, 1H, J = 3.2 Hz, ArH), 8.26 (d, 1H, = 8.0 Hz, ArH), 8.04 (s, 1H, ArH), 7.64 (s, 1H, ArH), 7.52 (dd, 1H, J! = 8.0 Hz, J2 = 3.2 Hz, ArH), 4.16 (s, 3H, -OCH3), 2.75 (s, 3H, -COCH3). 实施例 2、 l-(8-甲氧基喹啉 -6-基)乙醇(V a)
将化合物 IVa 1.02g(5mmol)溶于 50ml四氢呋喃,分次加入硼氢化纳 0.23g(6mmol), 室温反应 3小时。 加水 50ml , 乙酸乙酯 50 ml*3提取, 合并有机层, 干燥, 浓缩, 得 淡黄色固体 V a, 收率 95%, m.p. 51-53 °C。
1H- MR (δ, CDC13): 8.87 (dd, 1H, = 4.4 Hz, J2 = 2.0 Hz, ArH), 8.07 (dd, 1H, = 8.0 Hz, J2 = 2.0 Hz, ArH), 7.40 (dd, 1H, h = 8.0 Hz, J2 = 4.4 Hz, ArH), 7.32 (s, 1H, ArH), 7.09 (s, 1H, ArH), 5.04 (q, 1H, J = 6.0 Hz, -CHOHCH3), 4.84 (s, 1H, -CHOHCH3), 4.09 (s, 3H, -OCH3), 1.57 (d, 3H, = 6.0 Hz, -CHOHCH^). 实施例 3、 6-(l-氯乙基 )-8-甲氧基喹啉(Via)
将化合物 V a 1.4g(5mmol)溶解于 10ml二氯甲垸,加入二氯亚砜 1ml , 室温反应 12 小时。 加水 10ml , 分离有机层, 干燥, 浓缩, 得淡黄色油状物 Via, 收率 70%。
1H- MR (δ, CDC13): 9.03 (dd, 1H, ^ = 4.4 Hz, J2 = 1.6 Hz, ArH), 8.12 (dd, 1H, = 8.4 Hz, J2 = 1.6 Hz, ArH), 7.49 (dd, 1H, h = 8.4 Hz, J2 = 4.4 Hz, ArH), 7.38 (s, 1H, ArH), 7.13 (s, 1H, ArH), 4.89 (q, 1H, J = 6.0 Hz, -CHC1CH3), 3.98 (s, 3H, -OCH3), 1.64 (d, 3H, = 6.0 Hz, -CHCICH3). 实施例 4、 4-(l-(8-甲氧基喹啉 -6-基)乙基)吗啉(雨 a)
将化合物 Via 0.22g(lmmol)溶解于 5ml乙腈中, 加入吗啉 Vila 0.5ml , 回流反应 3 小时。 加水 10ml , 分离有机层, 干燥, 浓缩, 得黄色油状物雨 a, 收率 92%。
1H- MR (δ, CDC13): 8.83 (dd, 1Η, = 4.0 Hz, J2 = 2.0 Hz, ArH), 8.00 (dd, 1H, = 8.0 Hz, J2 = 2.0 Hz, ArH), 7.34 (dd, 1H, h = 8.0 Hz, J2 = 4.0 Hz, ArH), 7.23 (s, 1H, ArH), 7.11 (s, 1H, ArH), 4.04 (s, 3H, -OCH3), 3.61 (m, 5H, morpholine, -CHCH3), 2.32 (m, 4H, morpholine), 1.57 (d, 3H, = 6.4 Hz, -CHC¾). 实施例 5、 6-(l-吗啉基乙基) -8-羟基喹啉(IXa)
将化合物 Villa 0.26g(lmmol)加入 5ml氢漠酸中, 100°C反应 24小时。 用 NaHC03 调节 pH=8 , 乙酸乙酯 10ml*3提取, 合并有机层, 干燥, 浓缩, 柱层析分离 (石油醚: 乙酸乙酯: 三乙胺 =2: 1 : 0.1), 得到棕黄色油状物 IXa, 收率 45%。
1H- MR (δ, CDC13): 8.75 (s, 1H, ArH), 8.12 (d, 1H, = 8.4 Hz, ArH), 7.34 (dd, 1H, = 8.4 Hz, J2 = 5.2 Hz, ArH), 7.28 (s, 1H, ArH), 7.26 (d, 1H, J = 5.2 Hz, ArH), 3.72 (m, 4H, morpholine), 3.41 (q, 1H, J = 6.4 Hz, -CHCH3), 2.36 (m, 4H, morpholine), 1.41 (d, 3H, J = 6.4 Hz, - RCH3). 实施例 6、 6-(l-吗啉乙基)喹啉 -8-基-二甲基甲酰胺 (l a)
将化合物 IXa 0.11g(0.5mmol)溶解于 10ml四氢呋喃, 加入氢化纳 14mg(0.6mmol), 室温反应 4小时, 滴加 N,N-二甲基氨基甲酰氯 Xa 0.73mg(0.6mmol), 室温反应 12小 时。 减压蒸除溶剂, 加入 20ml水, 乙酸乙酯 20ml*3提取, 合并有机层, 干燥, 浓缩, 柱层析分离 (石油醚: 乙酸乙酯: 三乙胺 =2: 1 : 0.1),得到桔黄色油状物 IXa, 收率 42%。
1H- MR (δ, CDC13): 8.91 (d, 1H, = 4.4 Hz, ArH), 8.13 (d, 1H, = 8.0 Hz, ArH), 7.60 (s, 1H, ArH), 7.55 (s, 1H, ArH), 7.41 (dd, 1H, h = 8.0 Hz, J2 = 4.4 Hz, ArH), 3.72 (m, 4H, morpholine), 3.50 (d, 1H, = 5.6 Hz, -CHCH3), 3.30 (s, 3H, -NCH3), 3.09 (s, 3H, -NCH3), 2.50 (m, 4H, morpholine), 1.44 (d, 4H, = 5.6 Hz, -CHC¾)。 实施例 7、 6-(l-吗啉乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (l b)
操作过程参见实施例 6, 用 N-甲基 乙基氨基甲酰氯代替 N,N-二甲基氨基甲酰 氯。 得到黄色油状物 l b , 收率 51%。
1H- MR (δ, CDC13): 8.89 (d, 1H, = 4.0 Hz, ArH), 8.12 (d, 1H, = 8.0 Hz, ArH), 7.59 (s, 1H, ArH), 7.54 (d, 1H, J = 8.0 Hz, ArH), 7.39 (dd, 1H, = 8.0 Hz, J2 = 4.0 Hz, ArH), 3.72 (m, 5H, morpholine, -NCH2CH3), 3.47 (m, 2H, -NCH2CH3, -CHCH3), 3.27 (s, 1.5H,
-NCH3), 3.07 (s, 1.5H, -NCH3), 2.49 (m, 4H, morpholine), 1.42 (m, 4.5H, -CHC¾, -NCH2C¾), 1.25 (m, 1.5H, -NCH2C¾)。 实施例 8、 6-(l-吗啉乙基)喹啉 -8-基-二乙基甲酰胺 (I c)
操作过程参见实施例 6, 用 N,N-二乙基氨基甲酰氯代替 N,N-二甲基氨基甲酰氯。 得到黄色油状物 I c, 收率 59%。
1H- MR (δ, CDC13): 8.86 (d, IH, = 4.0 Hz, ArH), 8.10 (d, IH, = 8.4 Hz, ArH), 7.58 (s, IH, ArH), 7.53 (s, IH, ArH), 7.37 (dd, IH, J! = 8.4 Hz, J2 = 4.0 Hz, ArH), 3.71 (m, 4H, morpholine), 3.63 (d, 2H, = 7.2 Hz, -NCH2CH3), 3.45 (m, 3H, -NCH2CH3, -CHCH3), 2.49 (m, 4H, morpholine), 1.40 (m, 6H, - RCH3, -NCH2C¾), 1.25 (d, 3H, J = 7.2 Hz,
实施例 9、 6-(l-吗啉乙基)喹啉 -8-基-吡咯垸基 -1-甲酰胺 (I d)
操作过程参见实施例 6, 用吡咯垸基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。 得到 棕黄色油状物 I d, 收率 43%。
1H- MR (δ, CDC13): 8.92 (d, 1Η, = 2.4 Hz, ArH), 8.14 (d, IH, = 8.4 Hz, ArH), 7.60 (s, IH, ArH), 7.43 (dd, IH, ^ = 8.4 Hz, J2 = 2.4 Hz, ArH), 7.30 (s, IH, ArH), 4.14 (m, 2H, pyrrolidine), 3.82 (m, IH, pyrrolidine), 3.73 (m, 4H, morpholine), 3.56 (m, IH, pyrrolidine), 3.49 (m, IH, -CHCH3), 2.51 (m, 4H, morpholine), 2.00 (m, 4H, pyrrolidine), 1.45 (m, 3H, -CHCH3). 实施例 10、 6-(l-吗啉乙基)喹啉 -8-基-哌啶基 -1-甲酰胺 (I e)
操作过程参见实施例 6, 用哌啶基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。 得到棕 色油状物 I e, 收率 63%。
1H- MR (δ, CDC13): 8.89 (d, 1Η, = 4.0 Hz, ArH), 8.10 (d, IH, = 8.0 Hz, ArH), 7.42 (dd, IH, = 8.0 Hz, J2 = 4.0 Hz, ArH), 7.29 (s, IH, ArH), 7.17 (s, IH, ArH), 4.13 (m, 2H, piperidine), 3.74 (m, 6H, piperidine, morpholine), 3.43 (m, IH, -CHCH3), 2.49 (m, 4H, morpholine), 1.68 (m, 3H, -CHC¾), 1.42 (m, 4H, piperidine), 1.26 (m, 2H, piperidine). 实施例 11、 6-(l-吗啉乙基)喹啉 -8-基-吗啉基 -1-甲酰胺 (I f)
操作过程参见实施例 6, 用吗啉基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。 得到黄 色油状物 I f , 收率 61%。
¾- MR (δ, CDC13): 8.86 (s, IH, ArH), 8.11 (d, IH, J = 8.4 Hz, ArH), 7.58 (s, IH, ArH), 7.55 (s, IH, ArH), 7.37 (m, IH, ArH), 4.13 (m, 2H, piperidine), 3.74 (m, 12H, morpholine), 3.46 (q, IH, J = 6.4 Hz, -CHCH3), 2.47 (m, 4H, morpholine), 1.41 (d, 3H, J = 6.4 Hz, - RCH3).
实施例 12、 l-(8-甲氧基喹啉 -6-基) -N,N-二甲基乙胺 (雨 b)
操作过程参见实施例 4,用二甲胺盐酸盐代替吗啉。得黄色油状物雨 b , 收率 90%。 1H- MR (δ, CDC13): 8.93 (dd, 1H, = 4.4 Hz, J2 = 2.0 Hz, ArH), 8.07 (dd, 1H, = 8.0 Hz, J2 = 2.0 Hz, ArH), 7.40 (dd, 1H, h = 8.0 Hz, J2 = 4.4 Hz, ArH), 7.29 (s, 1H, ArH), 7.16 (s, 1H, ArH), 4.03 (s, 3H, -OCH3), 3.67 (q, 1H, J = 6.0 Hz, -CHCH3), 2.38 (s, 6H, -N(CH3)2), 1.57 (d, 3H, = 6.0 Hz, -CUCH3). 实施例 13、 6-(l- (二甲胺基)乙基) -8-羟基喹啉(IXb)
操作过程参见实施例 5。 以雨 b代替雨 a, 得黄色油状物 IXb , 收率 46%。
1H- MR (δ, CDC13): 8.75 (s, 1H, ArH), 8.13 (d, 1H, = 8.4 Hz, ArH), 7.41 (dd, 1H, = 8.4 Hz, J2 = 4.0 Hz, ArH), 7.23 (s, 1H, ArH), 7.13 (d, 1H, = 4.0 Hz, ArH), 3.71 (q, 1H, J = 6.8 Hz, -CHCH3), 2.28 (s, 6H, -N(CH3)2), 1.46 (d, 3H, = 6.8 Hz, -CHC¾). 实施例 14、 6-(l- (二甲胺基)乙基)喹啉 -8-基-二甲基甲酰胺(I g)
操作过程参见实施例 6, 用 IXb代替 IXa。 得到黄色油状物 I g, 收率 48%。
1H- MR (δ, CDC13): 8.89 (d, 1H, = 2.8 Hz, ArH), 8.12 (d, 1H, = 8.0 Hz, ArH), 7.60 (s, 1H, ArH), 7.51 (s, 1H, ArH), 7.39 (dd, 1H, h = 8.0 Hz, J2 = 2.8 Hz, ArH), 3.46 (q, 1H, J = 6.8 Hz, -CHCH3), 3.28 (s, 3H, -CON(CH3)2), 3.07 (s, 3H, -CON(CH3)2), 2.28 (s, 6H, -CHN(CH3)2\ 1.46 (d, 3H, J = 6.8 Hz, -CHC¾). 实施例 I5、 6-(l- (二甲胺基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I h)
操作过程参见实施例 14, 用 N-甲基 乙基氨基甲酰氯代替 N,N-二甲基氨基甲酰 氯。 得到棕黄色油状物 I h, 收率 51%。
1H- MR (δ, CDC13): 8.89 (d, IH, = 4.0 Hz, ArH), 8.12 (d, IH, = 8.0 Hz, ArH), 7.59 (s, IH, ArH), 7.52 (d, IH, J = 8.0 Hz, ArH), 7.38 (dd, IH, = 8.0 Hz, J2 = 4.0 Hz, ArH), 3.67 (m, IH, -NCH2CH3), 3.45 (m, 2H, -NCH2CH3,-CHCH3), 3.26 (s, 1.5H, -NCH3), 3.06 (s, 1.5H, -NCH3), 2.27 (s, 6H, -NCH3), 1.45 (m, 3H, -CHC¾), 1.38 (m, 1.5H, -NCH2C¾), 1.25 (m, 1.5H, -NCH2C¾). 实施例 16、 6-(l- (二甲胺基)乙基)喹啉 -8-基-二乙基甲酰胺 (Π)
操作过程参见实施例 14, 用 N,N-二乙基氨基甲酰氯代替 N,N-二甲基氨基甲酰氯。 得到黄色油状物 Π , 收率 58%。
1H- MR (δ, DMSO-i¾): 8.78 (dd, IH, J尸 4.0 Hz, J2 = 1.6 Hz, ArH), 8.25 (dd, IH, J尸 8.4 Hz, J2 = 1.6 Hz, ArH), 7.49 (dd, IH, J尸 8.4 Hz, J2 = 4.0 Hz, ArH), 7.37 (s, ArH), 6.96 (s, IH, ArH), 4.01 (q, 4H, = 7.2 Hz, -NCH2CH3), 3.99 (m, IH, -CHN(CH3)2), 2.16 (s, 6H, -CHN(CH3)2\ 1.35 (d, 3H, = 6.4 Hz, -CHC¾), 1.16 (t, 6H, = 7.2 Hz, -CHC¾). 实施例 17、 6-(l- (二甲胺基)乙基)喹啉 -8-基-吡咯垸基 -1-甲酰胺 (I j)
操作过程参见实施例 14,用吡咯垸基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。得到 棕黄色油状物 I j , 收率 41%。
1H- MR (δ, CDC13): 8.88 (dd, 1H, 尸 4.0 Hz, J2 = 1.6 Hz, ArH), 8.07 (dd, 1H, 尸 8.0 Hz, J2 = 1.6 Hz, ArH), 7.39 (dd, 1H, J尸 8.0 Hz, J2 = 4.0 Hz, ArH), 7.21 (s, ArH), 7.13 (s, 1H, ArH), 4.12 (t, 4H, J = 6.0 Hz, -CHN(CH3)2), 3.34 (m, 4H, pyrrolidine), 2.27 (s, 6H, -CHN(CH3)2\ 1.42 (t, 3H, = 6.0 Hz, -CHCH3), 1.23 (m, 4Η, pyrrolidine). 实施例 18、 6-(l- (二甲胺基)乙基)喹啉 -8-基-哌啶基 -1-甲酰胺 (I k)
操作过程参见实施例 14,用哌啶基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。得到棕 色油状物 I k, 收率 46%。
1H- MR (δ, CDC13): 8.87 (d, 1Η, = 6.8 Hz, ArH), 8.06 (d, 1H, = 8.4 Hz, ArH), 7.38
(dd, 1H, J尸 8.4 Hz, J2 = 6.8 Hz, ArH), 7.26 (d, 1H, = 1.6 Hz, ArH), 7.14 (d, 1H, = 1.6
Hz, ArH), 4.10 (m, 5H, -CHCH3, piperidine), 2.25 (m, 10H, piperidine, -CHNfCH3J2), 1.44
(d, 3Η, J = 6.8 Hz, -CUCH3). 实施例 I9、 6-(l- (二甲胺基)乙基)喹啉 -8-基-吗啉基 -1-甲酰胺 (I I)
操作过程参见实施例 14,用吗啉基 -1-甲酰氯代替 N,N-二甲基氨基甲酰氯。得到黄 色油状物 I I , 收率 59%。
1H- MR (δ, CDC13): 8.77 (d, 1H, J = 4.4 Hz, ArH), 7.96 (d, 1H, J = 8.4 Hz, ArH), 7.27 (dd, 1H, 尸 8.4 Hz, J2 = 4.4 Hz, ArH), 7.16 (d, 1H, = 1.6 Hz, ArH), 7.05 (d, 1H, = 1.6 Hz, ArH), 4.00 (q, 1H, = 6.4 Hz, -CHCH3,), 3.57 (t, 4H, = 4.8 Hz, morphine), 3.16 (t, 4H, = 4.8 Hz, morphine), 2.14 (s, 6H, - HN(CH3)2 1.32 (d, 3H, = 6.4 Hz, -CHC¾). 实施例 20、 N,N-二乙基 -l-(8-甲氧基喹啉 -6-基)乙胺 (雨 c)
操作过程参见实施例 4, 用二乙胺代替吗啉。 得黄色油状物雨 c, 收率 88%。
1H- MR (δ, CDC13): 8.98 (s, 1H, ArH), 8.18 (d, 1H, = 8.4 Hz, ArH), 7.52 (dd, 1H, = 8.4 Hz, J2 = 5.6 Hz, ArH), 7.40 (s, 1H, ArH), 7.22 (s, 1H, J = 5.6 Hz, ArH), 4.22 (s, 3H, -OCH3), 4.03 (q, 1H, J = 6.0 Hz, -CHCH3), 2.72 (m, 4H, -N(CH2CH3)2), 1.53 (d, 3H, J = 6.0 Hz, -CHCH3), 1.08 (m, 6Η, -N(CH2C¾)2). 实施例 21、 6-(l- (二乙胺基)乙基) -8-羟基喹啉(IXc)
操作过程参见实施例 5。 得黄色固体 IXc, 收率 46%。 m.p. 65-67°C。
1H- MR (δ, CDC13): 8.72 (s, 1H, ArH), 8.11 (d, 1H, J = 8.4 Hz, ArH), 7.39 (dd, 1H, = 8.4 Hz, J2 = 5.2 Hz, ArH), 7.32 (s, 1H, ArH), 7.20 (d, 1H, J = 5.2 Hz, ArH), 3.91 (q, 1H, J = 6.0 Hz, -CHCH3), 2.57 (m, 4H, -N(CH2CH3)2), 1.42 (d, 3H, = 6.0 Hz, -CUCH3), 1.01 (m, 6H, -N(CH2C¾)2). 实施例 22、 6-(l- (二乙基氨基)乙基)喹啉 -8-基 -甲基甲酰胺 (I m)
操作过程参见实施例 14, 用 N-乙基氨基甲酰氯代替 N,N-二甲基氨基甲酰氯, IXc 代替 IXb。 得到黄色油状物 I m, 收率 32%。
1H- MR (δ, CDC13): 8.89 (d, 1H, = 2.4 Hz, ArH), 8.09 (d, 1H, = 8.0 Hz, ArH), 7.41 (dd, 1H, J! = 8.0 Hz, J2 = 2.4 Hz, ArH ), 7.36 (s, 1H, ArH), 7.31 (s, 1H, ArH), 4.12 (d, 3H, J = 5.6 Hz, -NCH3), 3.96 (d, 1H, = 6.4Hz, -CHCH3), 2.72 (s, 4H, -N(CH2CH3)2), 1.48 (s, 3H, -CHCH3), 1.06 (d, 6Η, J = 6.4 Hz, -N(CH2CH3)2). 实施例 23、 6-(l- (二乙基氨基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I n)
操作过程参见实施例 14, Kc代替 Kb。 得到黄色油状物 I n, 收率 54%。
1H- MR (δ, CDC13): 8.89 (d, 1Η, = 4.0 Hz, ArH), 8.12 (d, 1H, = 8.0 Hz, ArH), 7.62 (s, 1H, ArH ), 7.60 (d, 1H, J = 6.8 Hz, ArH), 7.38 (dd, 1H, J2 = 8.0 Hz, J2 = 6.8 Hz, ArH), 3.99(d, 1H, J = 6.0 Hz, -CHCH3), 3.68 (m, 1H, -CONCH2CH3), 3.48 (m, 1H, -CONCH2CH3), 3.27 (s, 1.5H, -NCH3), 3.06 (s, 1.5H, -NCH3), 2.61 (q, 4H, J = 6.8 Hz, -CHN(CH2CH3)2), 1.44 (d, 3H, = 6.0 Hz, -CUCH3), 1.37 (m, 1.5H, -CONCH2C¾), 1.26 (m, 1.5H, -CONCH2C¾), 1.03 (t, 6H, = 6.8 Hz, -CHN(CH2CH3)2). 实施例 24、 N-甲基 -N-乙基 -l-(8—甲氧基喹啉—6—基)乙胺 (雨 d)
操作过程参见实施例 4, 用甲乙胺代替吗啉。 得黄色油状物雨 d, 收率 82%。 实施例 25、 6-(1- (乙基 (甲基)胺基)乙基) 羟基喹啉(IXd)
操作过程参见实施例 5。 得棕黄色油状物 IXd, 收率 44%。
1H- MR (δ, CDC13): 8.73 (d, 1H, J = 2.8, ArH), 8.10 (d, 1H, J = 8.4 Hz, ArH), 7.40 (dd, 1H, = 8.4 Hz, J2 = 2.8 Hz, ArH), 7.27 (s, 1H, ArH), 7.25 (s, 1H, ArH), 3.68 (q, 1H, J = 6.4 Hz, -CHCH3), 2.42 (q, 2H, J = 2.8, -N(CH3)CH2CH3), 2.16 (s, 3H, -N(C¾)CH2CH3), 1.43 (d, 3H, J = 6.4 Hz, -CHC¾), 1.04 (q, 3H, J = 2.8, -N(CH3)CH2C¾). 实施例 26、 6-(l- (乙基 (甲基)氨基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I o) 操作过程参见实施例 14, Kd代替 Kb。 得到黄色油状物 I o, 收率 55%。
1H- MR (δ, CDC13): 8.91 (d, 1H, J = 3.6 Hz, ArH), 8.10 (d, 1H, = 8.4 Hz, ArH), 7.43 (dd, 1H, J2 = 8.4 Hz, J2 = 3.6 Hz, ArH), 7.30 (s, 1H, ArH), 7.24 (s, 1H, ArH), 4.14 (m, 3.5H, -CONCH3, -CONCH2CH3, -CHCH3), 3.71 (m, 1.5H, -CONCH3), 3.50 (m, 1H, -CONCH2CH3), 2.58 (m, 2H, -NCH2CH3), 2.33 (s, 3H, -NCH3), 1.50 (d, 3H, = 6 Hz, -CHCH3), 1.26 (m, 3H, -CONCH2C¾), 1.10 (m, 3H, -NCH2C¾). 实施例 27、 8-甲氧基 -6-(l- (吡咯垸 -1-基)乙基)喹啉(雨 e)
操作过程参见实施例 4, 用吡咯垸代替吗啉。 得黄色油状物 Vllle, 收率 85%。 实施例 28、 6-(1- (吡咯垸 -1-基)乙基) -8-羟基喹啉(IXe)
操作过程参见实施例 5。 得黄色油状物 IXe, 收率 45%。
1H- MR (δ, CDC13): 8.73 (d, 1H, J = 4.0, ArH), 8.08 (d, 1H, J = 8.0 Hz, ArH), 7.39 (dd, 1H, J! = 8.0 Hz, J2 = 4.0 Hz, ArH), 7.30 (s, 1H, ArH), 7.17 (s, 1H, ArH), 3.30 (q, 1H, J = 6.0 Hz, -CHCH3), 2.42 (m, 4H, pyrrolidine), 1.77 (m, 4H, pyrrolidine), 1.46 (d, 3H, J = 6.0 Hz, -CUCH3). 实施例 29、 6-(l- (吡咯垸 -1-基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I p)
操作过程参见实施例 14, IXe代替 IXb。 得到黄色油状物 I p, 收率 52%。
1H- MR (δ, CDC13): 8.89 (d, 1H, = 4.0 Hz, ArH), 8.09 (d, 1H, = 8.8 Hz, ArH), 7.41 (dd, 1H, J! = 8.8 Hz, J2 = 4.0 Hz, ArH), 7.30 (s, 1H, ArH), 7.20 (s, 1H, ArH), 4.12 (m, 5H, -NCH3, -NCH2CH3), 3.37 (q, 1H, = 5.6 Hz, -CHCH3), 2.56 (m, 4H, pyrrolidine), 1.82 (m, 4H, pyrrolidine), 1.51 (d, 3H, J = 5.6 Hz, -CHC¾), 1.26 (t, 3H, J = 6.8 Hz, -NCH3). 实施例 30、 8-甲氧基 -6-(l- (哌啶 -1-基)乙基)喹啉(雨 f)
操作过程参见实施例 4, 用哌啶代替吗啉。 得黄色油状物 Vlllf, 收率 90%。 实施例 31、 6-(1- (哌啶 -1-基)乙基) -8-羟基喹啉(IXf)
操作过程参见实施例 5。 得淡黄色固体 IXf, 收率 52%。 m.p.104-106 °C。
1H- MR (δ, CDC13): 8.74 (d, 1H, J = 4.4, ArH), 8.12 (d, 1H, J = 8.4 Hz, ArH), 7.41 (dd, 1H, J! = 8.4 Hz, J2 = 4.4 Hz, ArH), 7.28 (s, 1H, ArH), 7.25 (s, 1H, ArH), 3.49 (q, 1H, J = 3.6 Hz, -CHCH3), 2.39 (m, 4H, piperidine), 1.55 (m, 4H, piperidine), 1.41 (m, 5H, -CHCH3, piperidine). 实施例 32、 6-(l- (哌啶 -1-基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I q)
操作过程参见实施例 14, IXf代替 IXb。 得到黄色油状物 I q, 收率 57%。
1H- MR (δ, CDC13): 8.87 (d, 1Η, = 2.8 Hz, ArH), 8.11 (d, 1H, = 8.4 Hz, ArH), 7.57 (s, 1H, ArH), 7.53 (d, 1H, J = 6.8 Hz, ArH), 7.37 (dd, 1H, J尸 8.4 Hz, J2 = 6.8 Hz, ArH), 3.68 (q, 1H, J = 6.8 Hz, -CHCH3), 3.56 (q, 1H, J = 6.8 Hz, -CH2CH3), 3.48 (q, 1H, J = 6.8 Hz, -CH2CH3), 3.26 (s, 1.5H, -NCH3), 3.06 (s, 1.5H, -NCH3), 2.42 (m, 4H, piperidine), 1.57 (m, 4H, piperidine), 1.44 (d, 3H, J = 6.8 Hz, -CHCH^), 1.39 (m, 2Η, piperidine), 1.25 (t, 1.5Η, = 6.8 Hz, -CH2CH3), 1.25 (t, 1.5Η, = 6.8 Hz, -CH2CH3). 实施例 33、 8-甲氧基 -6-(l-(4-甲基哌嗪 -1-基)乙基)喹啉(雨 g)
操作过程参见实施例 4, 用 N-甲基哌嗪代替吗啉。 得黄色油状物雨 g, 收率 90%。 实施例 34、 6—(1-(4—甲基哌嗪 -1-基)乙基) 羟基喹啉(IXg)
操作过程参见实施例 5。 得黄色固体 IXg, 收率 45%。 m.p. 117-119°C。
1H- MR (δ, CDC13): 8.72 (d, 1Η, J = 4.0, ArH), 8.09 (d, 1H, J = 8.0 Hz, ArH), 7.40
(dd, 1H, J! = 8.0 Hz, J2 = 4.0 Hz, ArH), 7.27 (s, 1H, ArH), 7.24 (s, 1H, ArH), 3.44 (q, 1H, J = 6.4 Hz, -CHCH3), 2.47 (m, 8H, 1-methylpiperazine), 2.29 (s, 3H, -NCH3), 1.40 (d, 3H, = 6.4 Hz, -CUCH3). 实施例 35、 6-(l-(4-甲基哌嗪 -1-基)乙基)喹啉 -8-基 -乙基 (甲基)甲酰胺 (I r) 操作过程参见实施例 14 , Kg代替 Kb。 得到黄色油状物 I r, 收率 40%。
1H- MR (δ, CDC13): 8.88 (d, 1H, = 3.2 Hz, ArH), 8.12 (d, 1H, = 8 Hz, ArH), 7.58 (s, 1H, ArH), 7.53 (d, 1H, = 8 Hz, ArH), 7.39 (dd, 1H, = 8.0 Hz, J2 = 3.2 Hz, ArH), 4.13 (q, 1H, J = 6.8 Hz, -CHCH3), 3.67 (q, 1H, J = 7.2 Hz, -NCH2CH3), 3.27 (m, 2.5H, -CONCH3, -NCH2CH3), 3.06 (s, 1.5H, -CONCH3), 2.67 (m, 8H, 1-Methyl-piperazine), 2.32 (s, 3H, -NCH3), 1.43 (d, 3H, J = 6.8 Hz, -CHCH3), 1.41 (t, 1.5H, J = 7.2 Hz, -NCH2C¾), 1.12 (t, 1.5H, J = 7.2 Hz, -NCH2C¾). 实施例 36、 化合物 I o的盐酸盐
取化合物 I o l .Og, 溶于 lOmL乙酸乙酯, 冰水洛中冷却至 0 °C , 滴加饱和 HC1乙 酸乙酯溶液, 离心, 得白色固体, 收率 70%。 实施例 37、 乙酰胆碱酯酶抑制活性测试方法
pCMV-AChE转染 HEK293细胞: 将 pCMV-AChE质粒加入无血清培养基, 加入 lipofectamineTM 2000转染试剂,混匀,配制转染液,静置 20min。取出培养后的 HEK293 细胞, 加无血清培养基, 缓慢滴加转染液, 放置 37 °C , 5%C02培养箱内 lh, 弃去培 养液, 加完全培养基, 置培养箱内培养。 72h后收集培养液, 12000rcf离心 5min, 取 上清液为酶液, 立即分析酶活性, 多余酶液分装后冻存于 -80 °C冰箱。
乙酰胆碱酯酶抑制活性测试:反应体系中加入 4μί酶液, 20μί抑制剂(即 Ia~Ir ), 50 L DTNB ( 0.1% ),加水补足到 150μί, 37 °C孵育 5min,加入 50 LATCh ( 0.5mmol/L ) 37 °C孵育 15min, 加入 50μί SDS ( 3% )终止反应, 在 412nm处测定 OD值, 平行三 份。 按照初筛结果选择化合物的七至九个浓度测定其酶抑制率, 以化合物摩尔浓度的 负对数与酶抑制率进行线性回归 (软件计算) 求取 IC50值。
:
Rivastigmine 8.26
If -N 0 -N 0 ***
\ _ / \ _ /
a. ***: 0.1~10μηιο1/ί; **: 10~50μηιο1/ί; *: 50~100μιηο1/ί。
从表 1中可以看出: (1)所有化合物对乙酰胆碱酯酶具有抑制作用。 (2)大部分的化 合物抑制活性在 10~50μιηο1/ί之间。 (3) 3个化合物的抑制活性在 0.1~10μιηο1/ί, 比 上巿药物 rivastigmine活性更好或相当。 实施例 38、 金属离子螯合能力测试方法
化合物的乙酰胆碱酯酶水解试验: 将 20μί化合物(即 IXa~IXr )的 PBS溶液加入 到 160 L PBS缓冲液中( pH=7.4 ),再加入 10(iL的 0.05%( v/v )的 Triton X-100和 20(iL 的乙酰胆碱酯酶匀浆, 在 37°C下孵育 48小时。 乙酸乙酯提取, 合并有机层, 无水硫 酸纳干燥。 减压蒸去溶剂, 得到化合物的乙酰胆碱酯酶水解产物
水解产物的金属离子螯合能力测试: 将水解产物溶解于 lmL甲醇中, 加入不同浓 度的铜或铁离子, 加水定容至 lOOmL, 0.5h后检测其在 200-600nm紫外吸收。 同时检 测水解产物的紫外光谱。 通过水解产物在不同浓度金属离子条件下的紫外图与化合物 的紫外图谱进行比较,判断其是否具有金属离子螯合能力。其中化合物 II的结果如下: 图 1中, 曲线 a为水解产物的紫外光谱, 曲线 b为水解产物加入铜离子后的紫外 光谱, 图中明显可以发现: 1 ) 最大吸收波长发生了位移; 2 )在水解产物的最大吸收 波长 240nm的吸收强度变化明显。 说明水解产物螯合了铜离子, 与之形成了复合物。 图 2中曲线 a为水解产物的紫外光谱, 曲线 b为水解产物加入铁离子后的紫外光谱, 同样说明了水解产物可以螯合铁离子。 实施例 39、 Αβ聚集抑制能力测试
将 Αβ肽用 1%氨水配成 O. lmM的溶液, 取 50μί加入至 50μί的金属离子水溶液 (O. lmM), 室温摇床 2分钟后, 加入 ΙΟΟμί的化合物 II水溶液 (O.lmM), 37°C摇床 48 小时。 使用透射电子显微镜分析 Αβ的聚集状态。
图 3为空白对照的 Αβ聚集状态, 图 4为加入化合物后 Αβ的聚集状态, 从图中可 以明显看出加入化合物后, 黑色斑块减少, 说明化合物能够抑制 Αβ的聚集。
总而言之, 该类新化合物不仅具有乙酰胆碱酯酶抑制活性和 Αβ聚集抑制能力, 其水解产物还具有金属离子螯合作用, 可以从多个靶点对老年痴呆进行治疗, 具有较 好的抗老年痴呆应用前景, 因而具有良好的商业价值。
无需进一步详细阐述, 相信釆用前面所公开的内容, 本领域技术人员可最大限度 地应用本发明。 因此, 前面的实施方案应理解为仅是举例说明, 而非以任何方式限制 本发明的范围。
Claims
杈 利 要 求 书
1、 一种 6,8-双取代喹啉化合物, 其特征在于, 结构如式 I所示:
其中, 1^或 R2的结构式独立地为 - R4R5;
R4或 R5独立地选自 H、 d-C4垸基、 d-C4烯基、 d-C4卤代垸基、 d-C4氧杂垸基、 d- 氮杂垸基、 芳基、 垸芳基、 垸氧基芳基、 卤代芳基, 或 、 R5与 N构成五元、 六元或七元环, 所述的五元、 六元或七元环为恶唑基、 吡咯基、 吡咯垸基、 咪唑基、 吡唑基、 哌啶基、 哌嗪基、 甲基哌嗪基、 高哌嗪基、 吗啉基或高哌啶基或其取代物;
R3独立地选自 d-do垸基、 d-do烯基、 Ci-Cio 代垸基、 C do氧杂垸基、 Ci-Cio 氮杂垸基; X为氧或硫。
2、 如权利要求 1所述的 6,8-双取代喹啉化合物, 其特征在于, 所述 R4、 R5 独立 地选自 H、 甲基、 乙基、 丙基、 异丙基, 或 、 R5与 N构成五元、 六元或七元环, 所述的五元、 六元或七元环为吡咯垸基、 哌啶基、 哌嗪基、 甲基哌嗪基、 高哌嗪基、 吗啉基或高哌啶基; R3独立地选自甲基、 乙基、 丙基、 异丙基、 乙烯基、 烯丙基。
3、 如权利要求 1所述的 6,8-双取代喹啉化合物或其药学上可接受的盐, 其特征在 于, 所述的 6,8-双取代喹啉化合物选自:
6-[(1-甲基氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[(1-甲基氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(1-甲基氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(1-甲基氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-甲基氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[(1-二甲氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[(1-二甲氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(1-二甲氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(1-二甲氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-二甲氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[(1-甲乙氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[(1-甲乙氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(1-甲乙氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(l-甲乙氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-甲乙氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[(1-二乙氨基)乙基] -8-甲氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-二甲氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-二乙氨基甲酰氧基喹啉
6-[(1-二乙氨基)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[1-(Γ-吗啉)乙基] -8-甲氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-二甲氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-二乙氨基甲酰氧基喹啉
6-[1-(Γ-吗啉)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6^-0 '-吡 嫁)乙基 ]-8-甲氨基甲酰氧基喹啉
S- -G '-P比 嫁)乙基] -8-二甲氨基甲酰氧基喹啉
5- -G '-P比 嫁)乙基] -8-甲乙氨基甲酰氧基喹啉
6^-0 ' 比 嫁)乙基] -8-二乙氨基甲酰氧基喹啉
6^—0 '-吡咯浣)乙基]—8—{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6- [1-(Γ-哌啶)乙基] 甲氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 二甲氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 甲乙氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] 二乙氨基甲酰氧基喹啉
6-[1-(Γ-哌啶)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-甲氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-二甲氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-甲乙氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-二乙氨基甲酰氧基喹啉
6-[1-(4'-甲基哌嗪)乙基] -8-{ 1-[(Γ-吗啉)甲酰基]氧基 }喹啉
6-[(1-二甲氨基)乙基]— 8-{ 1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉
6-[(1-二甲氨基)乙基] - 8-{ 1-[(Γ-哌啶)甲酰基]氧基 }喹啉
6-[(1-甲乙氨基)乙基] - 8-{ 1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉
6-[(1-甲乙氨基)乙基] - 8-{ 1-[(Γ-哌啶)甲酰基]氧基 }喹啉
6-[(1-二乙氨基)乙基] - 8-{ 1-[(Γ-吡咯垸)甲酰基]氧基 }喹啉, 或
6-[(1-二乙氨基)乙基] - 8-{ 1-[(Γ-哌啶)甲酰基]氧基 }喹啉。
、 如权利要求 1~3任一项所述的 6,8-双取代喹啉化合物在药学上可接受的盐, 其
特征在于: 所述的药学上可接受的盐为所述的 6,8-双取代喹啉化合物与无机酸、 有机 酸反应成盐。
5、如权利要求 4所述的 6,8-双取代喹啉化合物在药学上可接受的盐,其特征在于: 所述的药学上可接受的盐为盐酸盐、 氢漠酸盐、 氢碘酸盐、 硫酸盐、 硫酸氢盐、 磷酸 盐、 乙酸盐、 丙酸盐、 丁酸盐、 草酸盐、 酒石酸盐、 甲磺酸盐、 对甲苯磺酸盐、 富马 酸盐、 牛磺酸盐、 柠檬酸盐或琥珀酸盐。
6、 一种如权利要求 1~3任一项所述的 6,8-双取代喹啉化合物的制备方法, 其特征 在于, 包括以下步骤:
(1)如式 II的化合物与如式 III的化合物在第一有机溶剂中反应得到如式 IV的化合 物, 反应温度为室温至回流, 反应时间为 1~12小时;
(2)如式 IV的化合物与还原剂在第二有机溶剂中反应得到如式 V的化合物, 反应温 度为 -20~40°C , 反应时间 12~72小时;
(3)如式 V的化合物在第三有机溶剂中, 与二氯亚砜反应得到如式 VI的化合物, 反 应温度为室温至 150°C , 反应时间 1~24小时;
(4)如式 VI的化合物与如式 VII的化合物在第四有机溶剂中反应得到如式 VIII的化合 物, 反应温度为室温至回流, 反应时间 1~12小时;
(5)如式 VIII的化合物与氢漠酸反应得到如式 IX的化合物,反应温度为室温至 200°C , 反应时间 12 72小时;
(6)如式 IX的化合物在第五有机溶剂中,在缚酸剂的存在下与式 X的化合物反应得 到如式 I的化合物, 反应温度为 -50~50°C , 反应时间 1~24小时;
其中, 、 R2、 R3和 X的定义如权利要求 1~3任一项所述; Re通过步骤(1 ) 的 反应转化为 R3。
7、 如权利要求 6所述的 6,8-双取代喹啉化合物的制备方法, 其特征在于, 步骤 (1) 中所用的第一有机溶剂选用甲醇、 乙醇、 乙二醇中任一种或混合物;
步骤 (2)中所用的第二有机溶剂选用四氢呋喃、 乙醚、 丙酮、 丁酮中任一种或混合 物; 还原剂为硼氢化纳或氢化锂铝;
步骤 (3)中所用的第三有机溶剂选用乙腈、 丙酮、 三氯甲垸、 二氯甲垸中任一种或 混合物;
步骤 (4)中所用的第四有机溶剂选用乙腈、 丙酮、 丁酮、 二氯甲垸中任一种或混合 物;
步骤 (5)中氢漠酸质量百分比浓度为 10%-48%之间的任意浓度;
步骤 (6)中第五有机溶剂选用四氢呋喃、 丙酮、 二氯甲垸中任一种或混合物, 缚酸 剂选用碳酸钾、 碳酸氢钾、 碳酸纳、 丁基锂、 氢化纳中任一种或混合物。
8、一种如权利要求 1~3任一项所述的 6,8-双取代喹啉化合物或者如权利要求 4或 5 所述的 6,8-双取代喹啉化合物在药学上可接受的盐在制备治疗老年痴呆等退行性疾 病药物中的应用。
9、 一 6,8-双取代喹啉化合物, 其特征在于, 结构如式 IV所示:
6,8-双取代喹啉化合物, 其特征在于 结构如式 V所示:
6,8-双取代喹啉化合物, 其特征在于 结构如式 VI所示:
其中, R2或 R3的定义如权利要求 1或 2所述。
13、 一种 6,8-双取代喹啉化合物, 其特征在于, 结构如式 IX所示:
其中, R2 或 R3的定义如权利要求 1或 2所述。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410204002.2A CN103980194B (zh) | 2014-05-15 | 2014-05-15 | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 |
CN201410204002.2 | 2014-05-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015172722A1 true WO2015172722A1 (zh) | 2015-11-19 |
Family
ID=51272391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2015/078918 WO2015172722A1 (zh) | 2014-05-15 | 2015-05-14 | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN103980194B (zh) |
WO (1) | WO2015172722A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103980194B (zh) * | 2014-05-15 | 2016-09-07 | 浙江省医学科学院 | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 |
CN107417574B (zh) * | 2017-03-21 | 2019-12-03 | 浙江省医学科学院 | 2,4-双取代苯乙酮化合物及其旋光异构体、药学上可接受的盐及应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004007461A1 (en) * | 2002-07-16 | 2004-01-22 | Prana Biotechnology Limited | 8-hydroxy quinoline derivatives |
WO2006070394A1 (en) * | 2004-12-28 | 2006-07-06 | Council Of Scientific And Industrial Research | Substituted carbamic acid quinolin-6-yl esters useful as acetylcholinesterase inhibitors |
WO2010086860A2 (en) * | 2009-01-29 | 2010-08-05 | Yeda Research And Development Co. Ltd. | Neuroprotective multifunctional compounds and pharmaceutical compositions comprising them |
CN103980194A (zh) * | 2014-05-15 | 2014-08-13 | 浙江省医学科学院 | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9712761D0 (en) * | 1997-06-17 | 1997-08-20 | Chiroscience Ltd | Quinolines and their therapeutic use |
EP2566858A2 (en) * | 2010-05-04 | 2013-03-13 | Pfizer Inc. | Heterocyclic derivatives as alk inhibitors |
WO2012020389A1 (en) * | 2010-08-13 | 2012-02-16 | Varinel Inc | Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof |
-
2014
- 2014-05-15 CN CN201410204002.2A patent/CN103980194B/zh active Active
-
2015
- 2015-05-14 WO PCT/CN2015/078918 patent/WO2015172722A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004007461A1 (en) * | 2002-07-16 | 2004-01-22 | Prana Biotechnology Limited | 8-hydroxy quinoline derivatives |
WO2006070394A1 (en) * | 2004-12-28 | 2006-07-06 | Council Of Scientific And Industrial Research | Substituted carbamic acid quinolin-6-yl esters useful as acetylcholinesterase inhibitors |
WO2010086860A2 (en) * | 2009-01-29 | 2010-08-05 | Yeda Research And Development Co. Ltd. | Neuroprotective multifunctional compounds and pharmaceutical compositions comprising them |
CN103980194A (zh) * | 2014-05-15 | 2014-08-13 | 浙江省医学科学院 | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN103980194A (zh) | 2014-08-13 |
CN103980194B (zh) | 2016-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Huang et al. | Searching for the multi-target-directed ligands against Alzheimer’s disease: discovery of quinoxaline-based hybrid compounds with AChE, H3R and BACE 1 inhibitory activities | |
RU2663663C2 (ru) | Соль омекамтива мекарбила и способ ее получения | |
EP2331506A1 (de) | Neue benzamide, deren herstellung und deren verwendung als arzneimittel | |
DE102007034620A1 (de) | Neue B1-Antagonisten | |
JP5656834B2 (ja) | 肥満細胞トリプターゼインヒビターとしての[4−(5−アミノメチル−2−フルオロ−フェニル)−ピペリジン−1−イル]−[7−フルオロ−1−(2−メトキシ−エチル)−4−トリフルオロメトキシ−1h−インドール−3−イル]−メタノン | |
WO2023087611A1 (zh) | 一类依巴斯汀的盐及其制备方法和应用 | |
WO2006011669A1 (ja) | 新規桂皮酸関連化合物 | |
Wang et al. | Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease | |
JP5719852B2 (ja) | 7−クロロ−キノリン−4−アミン化合物、ならびにアミロイド斑の形成を含み、及び/又はappの代謝機能障害が生じる疾患の予防又は治療のためのそれらの使用 | |
KR20090018883A (ko) | 암치료용 히스톤 탈아세틸화 효소 저해제로서 엔-히드록시-3-(4-[3-페닐-에스-옥소-프로페닐]-페닐)-아크릴아미드 유도체 및 그 관련 화합물 | |
JP4199668B2 (ja) | Sst1アンタゴニスト活性を有するピペラジン誘導体 | |
Choi et al. | 6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE) | |
WO2015172722A1 (zh) | 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用 | |
KR101415174B1 (ko) | 신규한 벤조옥사졸계 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 포함하는 rage 수용체 관련 질환의 예방 또는 치료용 약학적 조성물 | |
US7999000B2 (en) | N-(2-amino-phenyl)-acrylamides | |
Nencetti et al. | Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors | |
EP2733144B1 (en) | Novel compound having parp inhibitory activity | |
NO314401B1 (no) | Nye, 4-substituerte piperidiner, farmasöytisk preparat inneholdende disse og anvendelse av dem for fremstilling av et medikament | |
WO2008019572A1 (en) | Meptazinol biligand derivatives and/or their salts, preparation method and uses thereof | |
WO2014047707A1 (pt) | Compostos heteroaromáticos, processo para preparar os compostos, composições farmacêuticas, usos e método de tratamento para as dores aguda e crônica | |
CS195652B2 (en) | Method of producing new 4-diphenylmethylen-1-hydroxy-benzylpiperidines | |
US10654802B2 (en) | Indoline derivatives and method for using and producing the same | |
CN110698411B (zh) | 一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途 | |
CN104003987A (zh) | 他克林-β-咔啉异二连体类多功能胆碱酯酶抑制剂 | |
WO2014063587A1 (zh) | 一类氟取代的环状胺类化合物及其制备方法、药物组合物和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15792284 Country of ref document: EP Kind code of ref document: A1 |
|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15792284 Country of ref document: EP Kind code of ref document: A1 |