KR20190066342A - Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient - Google Patents
Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient Download PDFInfo
- Publication number
- KR20190066342A KR20190066342A KR1020170165983A KR20170165983A KR20190066342A KR 20190066342 A KR20190066342 A KR 20190066342A KR 1020170165983 A KR1020170165983 A KR 1020170165983A KR 20170165983 A KR20170165983 A KR 20170165983A KR 20190066342 A KR20190066342 A KR 20190066342A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- substituted
- hydrogen
- compound
- present
- Prior art date
Links
- -1 honokiol derivative compounds Chemical class 0.000 title claims abstract description 35
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 27
- 239000004480 active ingredient Substances 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Chemical class 0.000 title claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 235000015872 dietary supplement Nutrition 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 208000024827 Alzheimer disease Diseases 0.000 claims description 24
- 108010053652 Butyrylcholinesterase Proteins 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 6
- 230000001713 cholinergic effect Effects 0.000 claims description 5
- 230000003930 cognitive ability Effects 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 102000021944 Butyrylcholinesterase Human genes 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 abstract description 15
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 abstract description 14
- 108090000322 Cholinesterases Proteins 0.000 abstract description 13
- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 abstract description 13
- 229940048961 cholinesterase Drugs 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 102000003914 Cholinesterases Human genes 0.000 abstract 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 102100032404 Cholinesterase Human genes 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 23
- 102100033639 Acetylcholinesterase Human genes 0.000 description 22
- 108010022752 Acetylcholinesterase Proteins 0.000 description 22
- 229940022698 acetylcholinesterase Drugs 0.000 description 22
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 17
- 229960004373 acetylcholine Drugs 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 239000002904 solvent Chemical group 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 13
- 108090000371 Esterases Proteins 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 229960001231 choline Drugs 0.000 description 11
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- 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 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000544 cholinesterase inhibitor Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 201000004810 Vascular dementia Diseases 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XYOPMGOBQPODTM-UHFFFAOYSA-N 2-butoxyethyl(trimethyl)azanium Chemical compound CCCCOCC[N+](C)(C)C XYOPMGOBQPODTM-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 2
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940039856 aricept Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- JHVLLYQQQYIWKX-UHFFFAOYSA-N benzyl 2-bromoacetate Chemical compound BrCC(=O)OCC1=CC=CC=C1 JHVLLYQQQYIWKX-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000008371 chromenes Chemical class 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 210000004129 prosencephalon Anatomy 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000037820 vascular cognitive impairment Diseases 0.000 description 2
- 210000004885 white matter Anatomy 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- HRBPBWKDJGGGCX-AWEZNQCLSA-N (2s)-5-(diaminomethylideneazaniumyl)-2-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]pentanoate Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N[C@@H](CCCN=C(N)N)C(O)=O HRBPBWKDJGGGCX-AWEZNQCLSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- WEQAAFZDJROSBF-UHFFFAOYSA-M 2-butanoylsulfanylethyl(trimethyl)azanium;iodide Chemical compound [I-].CCCC(=O)SCC[N+](C)(C)C WEQAAFZDJROSBF-UHFFFAOYSA-M 0.000 description 1
- HOZLOOPIXHWKCI-UHFFFAOYSA-N 2-chloro-n-methylacetamide Chemical compound CNC(=O)CCl HOZLOOPIXHWKCI-UHFFFAOYSA-N 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229940124596 AChE inhibitor Drugs 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000238426 Anostraca Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- 208000004481 Choline Deficiency Diseases 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 101710083761 Cholinesterase Proteins 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 241000256113 Culicidae Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000004552 Lacunar Stroke Diseases 0.000 description 1
- 206010051078 Lacunar infarction Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001673966 Magnolia officinalis Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 208000021752 choline deficiency disease Diseases 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 210000002233 diagonal band of broca Anatomy 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940108366 exelon Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000001497 healthy food Nutrition 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 235000014705 isoleucine Nutrition 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- VXPCQISYVPFYRK-UHFFFAOYSA-N profenamine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(CC)CC)C3=CC=CC=C3SC2=C1 VXPCQISYVPFYRK-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 210000002813 septal nuclei Anatomy 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000008371 vanilla flavor Substances 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 239000011579 vitamin B4 Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (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
Description
본 발명은 호노키올의 2번 또는 4번 위치의 히드록시기에 다양한 치환체가 치환된 신규한 O-치환된 호노키올 유도체 화합물 및 이의 용도에 관한 것으로, 본 발명의 O-치환된 호노키올 유도체 화합물을 포함하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물 및 퇴행성 질환의 예방 또는 개선용 건강보조식품 조성물에 관한 것이다.The present invention relates to a novel O-substituted monovalent quinolone derivative compound having various substituents in the hydroxyl group at the 2- or 4-position of the monovalent quinolone and the use thereof, and includes an O-substituted monovalent quinol derivative compound of the present invention And to a health supplement composition for preventing or ameliorating a degenerative disease.
의학산업의 발달과 급속한 경제성장에 따른 삶의 질이 향상됨과 동시에 각종 질병과 노인 인구가 증가하고 있다. 인간의 평균 수명은 연장되었지만 이에 따른 경제적 부담금이 가중되고 있다. 그중 하나가 바로 노인성 치매병이다. 그 중 50% 이상이 알츠하이머병(Alzheimer type, AD) 치매이다. 알츠하이머병(AD)은 비가역적이고 점진적으로 진행되는 뇌혈관질환 중의 하나로, 기억력, 언어 능력, 방향 감각, 주의력과 같은 인지 능력의 점진적 상실과 디프레션을 동반하는 나이와 관련된 퇴행성뇌신경계 질환(neurodegenerative disease)이다. 알츠하이머병(AD)의 발명원인이 정확하게 무엇인지는 밝혀지지 않았으며, 이에 따른 치료제도 없는 실정이다. 하지만 간접적으로 치매환자들의 뇌에서 정상적인 사람보다 아세틸콜린(ACh)을 합성하는 콜린아세틸트랜스퍼라제(ChAT)가 20~30%로 감소된 것으로 알려졌으며, 또한 신경(Neuron) 전달체인 아세틸콜린(ACh) 농도가 16~30%정도 감소한 것으로 확인되었다. With the development of the medical industry and the rapid economic growth, the quality of life has improved and various diseases and the elderly population are increasing. The average life span of humans has been extended, but the economic burden is increasing. One of them is senile dementia. More than 50% of them are Alzheimer type (AD) dementia. Alzheimer's disease (AD) is one of the irreversible and gradual progressive cerebrovascular diseases, characterized by gradual loss of cognitive abilities such as memory, language ability, directional sense, attention and degenerative neurodegenerative disease associated with depression, to be. The precise cause of the invention of Alzheimer's disease (AD) is unknown, and there is no treatment for it. However, indirectly, it has been reported that choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), is reduced to 20-30% in the brains of demented patients and that the neuron transport chain acetylcholine (ACh) And the concentration decreased by 16 ~ 30%.
알츠하이머병(AD)를 근본적으로 치료하기 위해서는 AD 환자의 뇌에서 발견되는 주 병변들의 제거와 인지학습기능의 손상을 예방하거나 억제할 수 있는 물질을 개발하여야 한다. 인지기능을 개선을 위해 시냅스 간격에 콜린성신경계를 보충하기 위한 방법으로는 a)아세틸콜린의 합성을 증진시키는 방법, b)아세틸콜린의 유리를 증진시키는 방법, c)아세틸콜린의 분해를 억제하는 방법 및 d)아세틸콜린 수용체를 직접 자극해 주는 방법 등이 있다. In order to fundamentally treat Alzheimer's disease (AD), substances that can prevent or inhibit the damage of cognitive learning function and the removal of major lesions found in the brain of patients with AD should be developed. Methods for supplementing the cholinergic nervous system at the synaptic interval to improve cognitive function include a) promoting the synthesis of acetylcholine, b) promoting the release of acetylcholine, c) inhibiting the degradation of acetylcholine And d) direct stimulation of acetylcholine receptors.
그러나, 알츠하이머병(AD) 환자에게 전구체인 콜린농도를 증가시키기 위해 콜린을 직접 주입하는 방식은 별다른 효과를 얻지 못하였다.However, direct injection of choline to increase the concentration of precursor choline in patients with Alzheimer's disease (AD) did not have much effect.
그로인해 간접적인 치료방법으로 신경(Neuron) 전달물질인 아세틸콜린을 가수분해하는 효소인 콜린에스터라제(ChE)를 억제하는 억제제를 이용하는 연구가 진행되어 오고 있다. 콜린에스터라제는 아세틸콜린에스터라제(AChE)와 부틸콜린에스터라제(BuChE)의 두 가지 형태를 갖는다.Therefore, studies have been conducted using an inhibitor that inhibits choline esterase (ChE), an enzyme that hydrolyzes acetylcholine, a neuron-transmitting substance, as an indirect treatment method. Choline esterase has two forms of acetylcholine esterase (AChE) and butylcholine esterase (BuChE).
AChE는 멤브레인-결합 효소(membrane-bound enzyme)로, 뇌, 근육 및 콜린성 뉴런에 존재한다. 포유류 뇌에 있어서, AChE의 대부분은 멤브레인-결합 G4 형태로 존재하며, 뉴런이 퇴화함에 따라 감소한다. 이는 콜린성 시냅스에서 AChE에 의해 신경전달물질인 아세틸콜린이 가수분해가 일어나게 된다. BChE는 신경교 (neuroglia)에서 발현되고, 장, 간, 신장, 심장, 폐 및 혈청에 존재한다. BChE는 에스테르기를 가진 화합물의 대사에 중요한 역할을 하는 것으로 알려져 있다. 이 효소는 AChE와 같이 아세틸콜린을 가수분해시킬 수 있으며, AD 환자의 경우 이 효소의 농도는 반응이 일어나도 감소되지 않아 AD를 더욱 악화시킬 수 있다.AChE is a membrane-bound enzyme, present in the brain, muscle and cholinergic neurons. In the mammalian brain, most of the AChE exists in a membrane-bound G4 form and decreases as neurons degenerate. In AChE, the neurotransmitter acetylcholine is hydrolyzed in cholinergic synapses. BChE is expressed in the neuroglia and is present in the intestine, liver, kidney, heart, lung and serum. BChE is known to play an important role in the metabolism of compounds with ester groups. This enzyme, like AChE, can hydrolyze acetylcholine. In the case of AD patients, the concentration of this enzyme does not decrease even when the reaction occurs, which can further aggravate AD.
이전에는 아세틸콜린에스터라제 억제제에 관한 합성이나 개발이 주가 되어 왔지만 최근 연구에서는 AD 뇌에서 부틸콜린에스터라제가 증가된다고 알려져 있어 치료제 개발에 높은 관심을 모으고 있다. 현재 각국에서 사용되고 있는 알츠하이머병(AD) 치료제는 이러한 아세틸콜린 분해효소(AChE) 억제제가 대부분이며, 타크린(tacrine, 상품명: 코그넥스(cognex)), 그리고 도네페질(donepezil, 상품명: 아리셉트(aricept)) 또는 리바스티그민(Rivastigmine, 상품명: 엑셀론(exelon)), 보다 최근에는 갈란타민(Galanthamine, 상품명: 레미닐(reminyl))으로서 출시되었으며 알츠하이머 환자의 인지 기능이 어느 정도 개선되었다. 이들 화합물은 여전히 일부 바람직하지 못한 부작용들, 예를 들어 떨림증, 현기증, 구토증, 간독성 등을 나타낸다.Previously, acetylcholinesterase inhibitors have been the subject of synthesis or development, but recent studies have shown that butylcholine esterase is elevated in AD brain, which is of great interest in the development of therapeutic agents. Currently, most of the ACE inhibitors that are used in various countries are tacrine (cognex), and donepezil (aricept (trade name: aricept) ), Or Rivastigmine (exelon), and more recently, Galanthamine (reminyl), and has improved the cognitive function of Alzheimer's patients to some extent. These compounds still exhibit some undesirable side effects, such as tremor, dizziness, vomiting, hepatotoxicity, and the like.
이제까지 대부분의 연구는 선택적 아세틸콜린에스테라제(AChE) 저해제들에도 촛점을 맞추어져 있었다. 수 년간 간과되어 왔지만, 부티릴콜린에스테라제(BuChE)도 아세틸콜린(ACh)을 가수분해할 수 있고 알츠하이머 병 환우에게 활성이 아세틸콜린 분해효소보다 높게 유지되어, AD의 병태생리학 및 증상학에서 중요한 역할을 할 것이다. 그러나 오늘날까지 선택적 BuChE 저해 활성을 갖는 매우 적은 화합물들이 보고되어 왔으며, 예로서 에토프로파진 (10-(2-디에틸아미노프로필) 페노티아진 염산염), 단실아르기닌 N-(3-에틸-1,5-펜탄디일)아미드 (DAPA), 페네틸노르심세린 및 WO 9902154 호 또는 EP 1251131 호에 개시된 화합물들이 있다.So far, most studies have focused on selective acetylcholinesterase (AChE) inhibitors. Although it has been overlooked for many years, butyrylcholinesterase (BuChE) can also hydrolyze acetylcholine (ACh), and its activity is maintained higher than that of acetylcholinesterase in Alzheimer's disease, and the pathophysiology and symptomatology of AD It will play an important role. To date, however, very few compounds have been reported with selective BuChE inhibitory activity, such as ethoprogin (10- (2-diethylaminopropyl) phenothiazine hydrochloride), dansylarginine N- (3-ethyl- 5-pentanediyl) amide (DAPA), phenethylnorthoserine and the compounds disclosed in WO 9902154 or EP 1251131.
한편, 상기 치매와 관련하여, 알쯔하이머 치매뿐 아니라 혈관성 치매의 인지기능 저하도 콜린 결핍과 관련이 있다. 콜린 형성을 담당하는 전뇌 기저부(basal forebrain)는 관통세동맥 (penetrating arterioles)에 의해 혈액공급을 받는데 이 혈관들은 고혈압에 쉽게 영향을 받는다. 콜린은 전뇌 기저부(basal forebrain)에 있는 브로카대각대(diagonal band of Broca), 내측 중격핵(medial septal nuclei), 그리고 마이너트기저핵(nucleus basalis of Meynert)에서 생성되며 대뇌 백질을 경유하여 대뇌 피질로 전달된다. 혈관성 치매환자의 전두엽에서 흔히 관찰되는 열공성 뇌경색이나 백질변성에 의하여 대뇌 피질로 가는 콜린 경로가 차단되어 실행기능(executive function)과 주의집중력에 장애가 초래될 수 있다. 생화학적으로는 혈관성 치매환자의 대뇌 피질, 해마, 선조체, 그리고 뇌척수액에서 아세틸콜린 활동도가 저하되었다. 이런 해부학적 또는 생화학적 증거가 혈관성 인지장애 환자에게 콜린에스테라제 억제제 효용성을 제시하였다. 현재 알쯔하이머 치매의 동반여부에 관계없이 혈관성 인지 장애 환자에게 콜린에스테라제 억제제 치료가 이용되고 있다. 즉, 이러한 콜린에스테라제 억제제로 아세틸콜린의 대사를 감소시키고 뇌에서의 콜린성 뇌신경 연접부위에서의 아세틸콜린의 작용을 증대시킨다.On the other hand, in relation to the above-mentioned dementia, not only Alzheimer's dementia but also cognitive dysfunction of vascular dementia is associated with choline deficiency. The basal forebrain, which is responsible for cholin formation, receives blood supply by penetrating arterioles, which are easily affected by hypertension. Choline is produced from the diagonal band of Broca, the medial septal nuclei, and the nucleus basalis of Meynert in the basal forebrain and is transmitted via the cerebral white matter to the cerebral cortex . The cholinergic pathway to the cerebral cortex is blocked by lacunar infarction or white matter degeneration commonly seen in the frontal lobe of patients with vascular dementia, which may lead to impairment of executive function and attention. Biochemically, acetylcholine activity decreased in cerebral cortex, hippocampus, striatum, and cerebrospinal fluid of patients with vascular dementia. These anatomical or biochemical evidence suggested the efficacy of cholinesterase inhibitors in patients with vascular cognitive impairment. Currently, treatment with cholinesterase inhibitors is used in patients with vascular cognitive impairment, whether or not they have Alzheimer's dementia. That is, this cholinesterase inhibitor reduces the metabolism of acetylcholine and enhances the action of acetylcholine at the cholinergic junction in the brain.
한편, 1978년에 4-O-메틸호노키올이 처음으로 분리되었으며, 4-O-메틸호노키올은 마그놀올과 함께 항균효과가 있고, 모기유충 및 브라인슈림프(brine shrimp)에 살충 효과가 있는 것으로 알려져 있으며, 한국등록특허 제10-932962호 및 제10-0926466호, 한국공개특허 제2009-94916호, 한국공개특허 2008-104760호에는 후박 (Magnolia officinalis Rehd. et Wils)의 줄기 및 잎으로부터 추출한 4-O-메틸호노키올이 아밀로이드 관련성 질환의 치료, 탈모 방지 및 모발의 생장의 촉진, 피부 미백 용도로 사용될 수 있음이 개시되어 있다.On the other hand, 4-O-methylhornokiol was first isolated in 1978, and 4-O-methylhornokiol has antimicrobial activity together with magnolol and has insecticidal effect on mosquito larvae and brine shrimp Korean Patent No. 10-932962 and No. 10-0926466, Korean Patent Laid-Open No. 2009-94916 and Korean Patent Publication No. 2008-104760 disclose a plant extract obtained from the stem and leaves of Magnolia officinalis Rehd. Et Wils It has been disclosed that 4-O-methylhornokiol can be used for treatment of amyloid-related diseases, prevention of hair loss, promotion of hair growth, skin whitening.
그러나, 종래에는 4-O-메틸호노키올에 대한 연구만 보고되어 있을 뿐, 다양한 치환체로 O-치환된 호노키올 유도체 화합물 및 이의 용도에 대해서는 아직 보고된 바 없다.However, only studies on 4-O-methylhornokiol have been reported in the past, and the use of O-substituted hornokiol derivatives with various substituents and their use has not been reported yet.
본 발명자들은 알츠하이머병 치료제를 개발하기 위해 연구를 수행한 결과, 호노키올의 2번 또는 4번 위치의 히드록시기에 다양한 치환체를 치환시킨 신규 O-치환된 호노키올 유도체 화합물이 콜린에스터라아제 활성을 저해하는 효과가 있음을 확인하였으며, 또한 치환체의 종류에 따라 콜린에스터라제 중 선택적으로 아세틸콜린에스터라제(AChE) 또는 부틸콜린에스터라제(BuChE) 활성을 저해하는 효과가 있음을 발견하고 본 발명을 완성하였다.The inventors of the present invention have conducted research to develop a therapeutic agent for Alzheimer's disease. As a result, the present inventors have found that a novel O-substituted monovalent choline derivative compound in which various substituents are substituted for hydroxyl groups at positions 2 or 4 of the honokiol, (AChE) or butyl cholinesterase (BuChE) activity selectively in choline esterase according to the type of the substituent, and found that the present invention .
따라서, 본 발명의 목적은 콜린에스터라제(ChEs) 저해 활성을 갖는 신규한 O-치환된 호노키올 유도체 화합물을 제공하는 것이다.Accordingly, an object of the present invention is to provide novel O-substituted monocyto derivative compounds having cholinesterase (ChEs) inhibitory activity.
본 발명의 다른 목적은 상기 O-치환된 호노키올 유도체 화합물을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a degenerative disease containing the O-substituted honokiol derivative compound as an active ingredient.
본 발명의 또 다른 목적은 상기 O-치환된 호노키올 유도체 화합물을 유효성분으로 함유하는 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품을 제공하는 것이다.It is still another object of the present invention to provide a health supplement for improving cognitive ability or improving degenerative diseases containing the O-substituted honokiol derivative compound as an active ingredient.
본 발명의 또 다른 목적은 상기 O-치환된 호노키올 유도체 화합물을 유효성분으로 함유하는 부티릴콜린에스터라제의 선택적 저해 활성을 위한 조성물을 제공하는 것이다.Yet another object of the present invention is to provide a composition for the selective inhibitory activity of butyrylcholinesterase containing the O-substituted honokiol derivative compound as an active ingredient.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 O-치환된 호노키올 유도체 화합물을 제공한다:An aspect of the present invention provides an O-substituted monovalent chromene derivative represented by the following formula
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
R1 및 R2는 서로 독립적으로 수소, C1-C7알킬, 시아노C1-C7알킬 또는 -(CH2)mCOR3이고;R 1 and R 2 are independently of each other hydrogen, C 1 -C 7 alkyl, cyano C 1 -C 7 alkyl or - (CH 2 ) m COR 3 ;
R3는 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR4R5이고;R 3 is C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 4 R 5 ;
m은 1 내지 5의 정수이고;m is an integer from 1 to 5;
R4 및 R5는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이고;R 4 and R 5 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;
단, R1과 R2가 동시에 수소 또는 C1-C7알킬인 경우 및 R1이 수소이고 R2가 C1-C7알킬인 경우는 제외된다.Provided that when R 1 and R 2 are simultaneously hydrogen or C 1 -C 7 alkyl and R 1 is hydrogen and R 2 is C 1 -C 7 alkyl,
본 발명의 다른 측면은 상기 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of a degenerative disease containing the O-substituted honokiol derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 측면은 상기 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품을 제공한다.Another aspect of the present invention provides a health supplement for improving cognitive ability or improving degenerative diseases, which comprises the O-substituted honokiol derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 측면은 하기 화학식 2로 표시되는 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 부티릴콜린에스터라제의 선택적 저해 활성을 위한 조성물을 제공한다.Another aspect of the present invention relates to a composition for selective inhibitory activity of butyrylcholinesterase comprising an O-substituted monovalent choline derivative compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient to provide.
[화학식 2](2)
상기 화학식 2에서,In Formula 2,
R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고;One of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 ;
R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고;R 6 and R 7 are each independently C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 8 R 9 ;
R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이다.R 8 and R 9 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl.
본 발명의 O-치환된 호노키올 유도체 화합물은 호노키올의 2번 또는 4번 위치의 히드록시기에 다양한 치환체가 치환된 신규한 구조의 화합물이다.The O-substituted monocytoin derivative compound of the present invention is a novel structure compound in which various substituents are substituted in the hydroxyl group at position 2 or 4 of the honokiol.
본 발명의 O-치환된 호노키올 유도체 화합물은 인체에 무해하고 콜린에스터라제의 활성을 저해하여 퇴행성 질환, 구체적으로 파킨슨 병, 알츠하이머병 등의 뇌신경 질환의 예방 및 치료에 사용할 수 있을 뿐만 아니라, 퇴행성 질환을 개선시키거나 학습능력 및 기억력을 개선시키는 건강보조식품으로도 활용 가능하다.The O-substituted monocytoin derivative compound of the present invention is harmless to human body and inhibits the activity of choline esterase and can be used for prevention and treatment of neurodegenerative diseases such as degenerative diseases, specifically Parkinson's disease and Alzheimer's disease, They can also be used as health supplements to improve degenerative diseases or improve learning and memory.
특히, 본 발명의 O-치환된 호노키올 유도체 화합물은 AChE 저해제에 의한 부작용이 적을 뿐만 아니라 알츠하이머병 환자의 뇌에서 활성이 높아 콜린에스터라제 형태 중 최근 많은 관심을 가지고 있는 BuChE만을 선택적으로 저해함과 동시에 아주 강력한 저해활성을 가지고 있으므로, 퇴행성 질환의 예방 및 치료용 약제학적 조성물 및 인지능력 개선 또는 퇴행성 질환의 개선용 건강보조식품의 유효성분으로 사용가능하다.In particular, the O-substituted monocytoin derivative compounds of the present invention are not only less adverse to AChE inhibitors, but also have a high activity in the brain of Alzheimer's disease patients, thereby selectively inhibiting only BuChE, which has recently attracted much attention in the form of choline esterase , It can be used as an active ingredient of a pharmaceutical composition for prevention and treatment of degenerative diseases and a health supplement for improving cognitive ability or improving degenerative diseases.
이하, 본 발명에 대하여 보다 구체적으로 설명한다. 이 때 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.Hereinafter, the present invention will be described in more detail. Unless otherwise defined, technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the following description, And a description of the known function and configuration will be omitted.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 O-치환된 호노키올 유도체 화합물을 제공한다:An aspect of the present invention provides an O-substituted monovalent chromene derivative represented by the following formula
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
R1 및 R2는 서로 독립적으로 수소, C1-C7알킬, 시아노C1-C7알킬 또는 -(CH2)mCOR3이고;R 1 and R 2 are independently of each other hydrogen, C 1 -C 7 alkyl, cyano C 1 -C 7 alkyl or - (CH 2 ) m COR 3 ;
R3는 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR4R5이고;R 3 is C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 4 R 5 ;
m은 1 내지 5의 정수이고;m is an integer from 1 to 5;
R4 및 R5는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이고;R 4 and R 5 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;
단, R1과 R2가 동시에 수소 또는 C1-C7알킬인 경우 및 R1이 수소이고 R2가 C1-C7알킬인 경우는 제외된다.Provided that when R 1 and R 2 are simultaneously hydrogen or C 1 -C 7 alkyl and R 1 is hydrogen and R 2 is C 1 -C 7 alkyl,
본 발명에 따른 화학식 1의 O-치환된 호노키올 유도체 화합물은 호노키올의 2번 또는 4번 위치의 히드록시기에 다양한 치환체가 치환된 신규 구조의 화합물로서, 콜린에스터라제, 즉 아세틸콜린에스터라제(AChE) 또는 부틸콜린에스터라제(BuChE) 저해 활성을 가지고 있어 퇴행성 질환의 예방 또는 치료용 약제학적 조성물의 유효성분으로 유용하다. The O-substituted monocytoin derivative compound of Formula 1 according to the present invention is a novel compound having various substituents on the hydroxyl group at the 2- or 4-position of the honokiol, and is a choline esterase, that is, acetylcholine esterase (AChE) or butyl choline esterase (BuChE) inhibitory activity, and is useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of a degenerative disease.
본 명세서에 기재된 용어 「알킬」은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소 라디칼을 의미하는 것으로, 이러한 알킬 라디칼의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 헥실 등을 포함하지만 이에 한정되지는 않는다.The term " alkyl " as used herein refers to a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, examples of which include methyl, ethyl, Butyl, pentyl, hexyl, and the like.
본 명세서에 기재된 용어 「시아노알킬」은 알킬에 존재하는 하나 이상의 수소가 시아노(-CN)로 치환된 것을 의미한다.The term " cyanoalkyl ", as used herein, means that at least one hydrogen present on the alkyl is replaced by cyano (-CN).
본 명세서에 기재된 용어 「알콕시」는 산소와 알킬이 결합된 1가의 -O-알킬 라디칼을 의미하는 것으로, 여기서 ‘알킬’은 상기 정의한 바와 같다. 이러한 알콕시 원자단의 예는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시 등을 포함하지만 이에 한정되지는 않는다.The term " alkoxy ", as used herein, refers to a monovalent -O-alkyl radical which is linked to oxygen and alkyl, wherein alkyl is as defined above. Examples of such alkoxy atomic groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.
본 명세서에 기재된 용어 「아릴」는 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 유기 라디칼로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합고리계를 포함하며, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 포함한다. 구체적인 예로 페닐, 나프틸, 비페닐, 인데닐(indenyl) 등을 포함하지만, 이에 한정되지는 않는다. The term " aryl ", as used herein, refers to an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, with a single or fused ring containing, suitably 4-7, preferably 5 or 6 ring atoms in each ring A ring system, and a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, indenyl, and the like.
본 명세서에 기재된 용어 「아릴알킬」은 1, 2 또는 3 개의 고리를 갖는 방향족 탄소환이 치환되어 있는 알킬기를 의미하는 것으로, 벤질 등이 있으며, 이에 한정되지는 않는다.The term " arylalkyl ", as used herein, refers to an alkyl group substituted with aromatic carbocyclic rings having one, two or three rings, including, but not limited to, benzyl.
본 명세서에 기재된 용어 「아릴옥시」는 산소와 아릴이 결합된 1가의 라디칼을 의미하는 것으로, 여기서 ‘아릴’은 상기 정의한 바와 같다. 이러한 아릴옥시 라디칼의 예는 페녹시, 나프톡시 등을 포함하지만 이에 한정되지는 않는다.The term " aryloxy ", as used herein, means a monovalent radical that is bound to oxygen and aryl, where " aryl " is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.
본 명세서에 기재된 용어 「아릴알킬옥시」는 아릴알킬의 알킬과 산소가 결합된 1가의 라디칼을 의미하는 것으로, 여기서 ‘아릴알킬’은 상기 정의한 바와 같다. 이러한 아릴알킬옥시 라디칼의 예는 벤질옥시 등을 포함하지만 이에 한정되지는 않는다.The term " arylalkyloxy ", as used herein, means a monovalent radical of an arylalkyl to which alkyl and oxygen are bonded, wherein the term " arylalkyl " is as defined above. Examples of such arylalkyloxy radicals include, but are not limited to, benzyloxy and the like.
본 발명의 일 실시예에 있어서, 상기 R1은 C1-C7알킬이고 R2는 수소일 수 있다.In one embodiment of the present invention, R 1 is C 1 -C 7 alkyl and R 2 can be hydrogen.
특히, 상기 화학식 1의 O-치환된 호노키올 유도체 화합물에서 R1은 C1-C7알킬이고 R2는 수소인 경우 콜린에스터라제(ChE) 형태 중 선택적으로 아세틸콜린에스터라제(AChE)에 대해 우수한 저해활성 특성을 가진다.Particularly, in the O-substituted monovalent choline derivative of Formula 1, when R 1 is C 1 -C 7 alkyl and R 2 is hydrogen, the cholinesterase (ChE) form is selectively substituted for acetylcholinesterase (AChE) And has excellent inhibitory activity characteristics.
본 발명의 일 실시예에 있어서, 상기 R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고, R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고, R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴일 수 있다.In one embodiment of the present invention, one of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 , R 6 and R 7 are each independently a C1-C7 alkoxy, C6-C12 aryloxy, C6-C12 aryl C1-C7 alkyloxy, hydroxy or -NR 8 R 9 and, R 8 and R 9 is hydrogen, C1-C7 alkyl, or each independently C6- Lt; / RTI > aryl.
특히, 상기 화학식 1의 O-치환된 호노키올 유도체 화합물에서 R1 및 R2 중 하나가 -CH2COR6이고, 나머지 하나가 수소, C1-C7알킬 또는 -CH2COR7이고, R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고, R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴인 경우 콜린에스터라제(ChE) 형태 중 선택적으로 부티릴콜린에스터라제(BuChE)에 대해 우수한 저해활성 특성을 가진다.In particular, the Formula 1 of O- substituted hono one of R 1 and R 2 in kiol derivative compound is -CH 2 COR 6, the other one is hydrogen, C1-C7 alkyl, or -CH 2 COR 7, R 6, and R 7 are each independently selected from C1-C7-alkoxy, C6-C12 aryloxy, C6-C12 aryl C1-C7 alkyloxy, hydroxy and hydroxy, or -NR 8 R 9, R 8 and R 9 are hydrogen, C1- each independently C7 < / RTI > alkyl or C6-C12 aryl, it has excellent inhibitory activity against butyrylcholine esterase (BuChE) in the form of choline esterase (ChE).
본 발명의 일 실시예에 있어서, 상기 R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고, R6 및 R7은 각각 독립적으로 C1-C7알콕시 또는 -NR8R9이고, R8 및 R9는 각각 독립적으로 수소 또는 C1-C7알킬일 수 있다.In one embodiment of the present invention, one of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 , R 6 and R 7 are each independently with a C1-C7 alkoxy, or -NR 8 R 9, R 8 and R 9 may be each independently hydrogen or C1-C7 alkyl.
본 발명의 일 실시예에 있어서, 상기 O-치환된 호노키올 유도체 화합물은 하기 구조로부터 선택될 수 있으나, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the O-substituted honokiol derivative compound may be selected from the following structures, but is not limited thereto.
본 발명에 따른 상기 O-치환된 호노키올 유도체 화합물들은, 이후 설명하는 바와 같이, 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있으며, 하기의 제조방법들은 일부 예시에 지나지 않으며, 그 이외의 방법들도 존재할 수 있음은 물론이다.The O-substituted monovalent chromene derivative compounds according to the present invention can be prepared by various methods based on known methods and / or techniques of organic synthesis, as will be described later, and the following production methods It is to be understood that the present invention is not limited thereto and other methods may be present.
예를 들어, 상기 화학식 1의 O-치환된 호노키올 유도체 화합물들은 하기와 같은 반응식으로 합성될 수 있다:For example, the O-substituted monovalent derivatives of the formula 1 can be synthesized by the following reaction scheme:
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서, Hal은 할로겐이고, R1 및 R2는 상기 화학식 1에서의 정의와 동일하다.In the above Reaction Scheme 1, Hal is halogen and R 1 and R 2 are the same as defined in Chemical Formula 1 above.
경우에 따라 상기 반응 생성물을 통상적인 방법, 예를 들어, 재결정과 크로마토그래피를 이용하여 분리 정제할 수 있다.In some cases, the reaction product can be separated and purified by a conventional method, for example, recrystallization and chromatography.
본 발명에 따른 상기 화학식 1의 O-치환된 호노키올 유도체 화합물들을 포함하는 하나의 바람직한 약학적으로 허용 가능한 형태는 약학 조성물 중의 형태를 포함하여 결정 형태이다. One preferred pharmaceutically acceptable form of the O-substituted monocytoin derivative compounds of Formula 1 according to the present invention is crystalline forms including forms in pharmaceutical compositions.
본 발명에 따른 상기 화학식 1의 O-치환된 호노키올 유도체 화합물은 물 또는 기타 유기 용매와 함께 수화물 또는 용매화물을 형성할 수 있다. 이러한 수화물 또는 용매화물도 마찬가지로 본 발명의 범주 내에 포함된다. 염 및 용매화물의 경우에 추가적인 이온 및 용매 잔기는 또한 무독성이어야 한다. 본 발명의 화합물은 상이한 동질이상 형태로 존재할 수 있으며, 본 발명은 상기와 같은 모든 형태들을 포함하고자 한다.The O-substituted monochiol derivative of Formula 1 according to the present invention may form a hydrate or a solvate together with water or other organic solvent. Such hydrates or solvates are likewise included within the scope of the present invention. In the case of salts and solvates, the additional ion and solvent moieties should also be non-toxic. The compounds of the present invention may exist in different isoforms, and the present invention encompasses all such forms.
상기 본 발명에 따른 신규 O-치환된 호노키올 유도체 화합물, 그의 염, 그의 용매화물 또는 전구약물은 우수한 콜린에스테라제 억제 작용을 나타낸다.The novel O-substituted monocytoin derivative compound according to the present invention, a salt thereof, a solvate thereof, or a prodrug thereof show excellent cholinesterase inhibiting action.
본 발명의 다른 측면은 상기 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of a degenerative disease containing the O-substituted honokiol derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 실시예에 있어서, 상기 퇴행성 질환은 구체적으로 파킨슨 병, 알츠하이머병과 같은 뇌신경질환을 포함한다.In one embodiment of the present invention, the degenerative disease specifically includes neurological diseases such as Parkinson's disease and Alzheimer's disease.
본 발명의 일 실시예에 있어서, 상기 약제학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레인산, 말론산, 타르타르산, 글루콘산, 락트산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염, 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 등을 포함한다. In one embodiment of the present invention, the pharmaceutically acceptable salt may be prepared by a conventional method in the art, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, Salts with inorganic acids such as hydrochloric acid, hydrobromic acid and carbonic acid, salts with inorganic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, Salts with organic acids such as acetylsalicylic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline, Salts with sulfonic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like, metal salts by reaction with alkali metals such as sodium and potassium, And the like salts.
본 발명의 일 실시예에 있어서, 상기 약제학적 조성물은 상기 화학식 1로 표시되는 O-치환된 호노키올 유도체 화합물 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구 투여용 제제 또는 비경구 투여용 제제로 제조하여, 상기 퇴행성 질환의 치료에 사용될 수 있다. In one embodiment of the present invention, the pharmaceutical composition comprises a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and / or adjuvant in the O-substituted monocytoin derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof, Excipients and the like to prepare preparations for oral administration or parenteral administration preparations such as tablets, capsules, troches, liquids and suspensions which are customary in the pharmaceutical field and can be used for the treatment of the above-mentioned degenerative diseases have.
본 발명의 일 실시예에 있어서, 상기 약제학적 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소듐 알진산염, 메틸셀룰로오스, 소듐 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. 이러한 부형제의 비율 및 성질은 선택된 정제의 용해도 및 화학적 특성, 선택된 투여경로 및 표준 약제 실무에 의해 결정될 수 있다.In one embodiment of the present invention, excipients that can be used in the pharmaceutical composition include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, , Fragrances, and the like. Examples of suitable additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. The ratios and properties of such excipients may be determined by the solubility and chemical properties of the selected tablet, the route of administration selected, and the standard pharmaceutical practice.
본 발명의 일 실시예에 있어서, 상기 화학식 1로 표시되는 O-치환된 호노키올 유도체 화합물의 인체에 대한 투여용량은 총 1일 용량 범위는 0.01 내지 1000 ㎎/㎏/일(day) 일 수 있으나, 이는 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In one embodiment of the present invention, the dose of the O-substituted monovalent guanole derivative compound represented by Formula 1 may be 0.01-1000 mg / kg / day for a total daily dose, , Which may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity, and may be administered once or several times a day at certain intervals according to the judgment of a doctor or pharmacist.
본 발명의 또 다른 측면은 상기 화학식 1로 표시되는 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 인지능력 개선 또는 알츠하이머병 또는 퇴행성 질환의 개선용 건강보조식품을 제공한다.Another aspect of the present invention relates to a method for improving cognitive function or improving Alzheimer's disease or degenerative disease comprising an O-substituted monovalent quinol derivative compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Provide food.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.
본 발명의 또 다른 측면은 하기 화학식 2로 표시되는 O-치환된 호노키올 유도체 화합물 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 함유하는 부티릴콜린에스터라제의 선택적 저해 활성을 위한 조성물을 제공한다.Another aspect of the present invention relates to a composition for selective inhibitory activity of butyrylcholinesterase comprising an O-substituted monovalent choline derivative compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient to provide.
[화학식 2](2)
상기 화학식 2에서,In Formula 2,
R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고;One of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 ;
R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고;R 6 and R 7 are each independently C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 8 R 9 ;
R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이다.R 8 and R 9 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl.
본 발명의 일 실시예에 있어서, 상기 R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고, R6 및 R7은 각각 독립적으로 C1-C7알콕시 또는 -NR8R9이고, R8 및 R9는 각각 독립적으로 수소 또는 C1-C7알킬일 수 있다.In one embodiment of the present invention, one of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 , R 6 and R 7 are each independently with a C1-C7 alkoxy, or -NR 8 R 9, R 8 and R 9 may be each independently hydrogen or C1-C7 alkyl.
이하, 실시예 및 실험예를 통해 본 발명을 상세히 설명한다. 단, 하기의 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following Examples.
[실시예 1] 화합물 1의 제조[Example 1] Preparation of Compound 1
호노키올(honokiol) (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.92g, 2.8mmol) 및 아이오도메탄 (0.17mL, 2.8mol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 디클로로메탄(DCM)을 이용하여 워-컵(work-up)한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=49:2:49 v:v:v, Rf =0.35)로 정제시켜 화합물 1를 수득하였다(노란색 액상, 34mg, 6.5% yield).Hono kiol (honokiol) (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.92g, 2.8mmol ) and iodo methane was added (0.17mL, 2.8mol) was reacted at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was worked-up with water and dichloromethane (DCM), and the obtained organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (DCM: Ether: HEX = 49: 2: 49 v: v: v, Rf = 0.35) 1 (yellow liquid phase, 34 mg, 6.5% yield).
1H NMR (CDCl3, 400MHz) δ 3.42(dd, J=6.4Hz, 36.8Hz, 4H), 3.78(s, 3H), 4.96(s, 1H), 5.07(m, 2H), 5.19(m, 2H), 6.02(m, 2H), 6.84(d, J=8Hz, 1H), 6.89(d, J=8Hz, 1H), 7.09(s, 1H), 7.26(m, 1H), 7.31(dd, J=2.4Hz, 8.0Hz, 1H) 1 H NMR (CDCl 3, 400MHz ) δ 3.42 (dd, J = 6.4Hz, 36.8Hz, 4H), 3.78 (s, 3H), 4.96 (s, 1H), 5.07 (m, 2H), 5.19 (m, (M, 2H), 6.02 (m, 2H), 6.84 (d, J = 8 Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 7.09 J = 2.4 Hz, 8.0 Hz, 1H)
[실시예 2] 화합물 2의 제조[Example 2] Preparation of Compound 2
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA(0.5mL, 3.76mmol), 메틸클로로아세테이트 (1.88mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=6:2:22 v:v:v, Rf =0.83)로 정제시켜 화합물 2를 수득하였다(흰색 액상, 210mg, 27% yield).Hono kiol (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.88mmol), TEA (0.5mL, 3.76mmol), was added methyl chloroacetate (1.88mmol) and KI (3.76mmol) at room temperature And reacted for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.83) to give Compound 2 (white liquid, 210 mg, 27% yield).
1H NMR (CDCl3, 400MHz) δ 3.42(m, 4H), 3.75(s, 3H), 3.80(s, 3H), 3.80(s, 3H), 4.54(s, 2H), 5.07(m, 4H), 6.00(m, 2H), 6.76(d, J=9.28Hz, 1H), 6.78(d, J=8.4Hz, 1H), 7.05(d, J=8.3Hz, 1H), 7.12(s, 1H), 7.12(s, 1H), 7.41(m, 2H); 13C NMR (CDCl3, 100MHz) δ 34, 39, 52(2C), 65, 66, 111, 113, 115.5, 115.7, 128, 128.4, 128.8, 130, 131.2, 131.4, 133(2C), 136, 137, 153, 154, 169(2C); ESI-MS: m/z [M+Na]+433.2(calcd.410.46) 1 H NMR (CDCl 3, 400MHz ) δ 3.42 (m, 4H), 3.75 (s, 3H), 3.80 (s, 3H), 3.80 (s, 3H), 4.54 (s, 2H), 5.07 (m, 4H J = 8.4 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H, ), 7.12 (s, 1 H), 7.41 (m, 2 H); 13 C NMR (CDCl 3 , 100 MHz)? 34,39, 52 (2C), 65, 66, 111, 113, 115.5, 115.7, 128, 128.4, 128.8, 130, 131.2, 131.4, 137, 153, 154, 169 (2C); ESI-MS: m / z [M + Na] < + > 433.2 (calcd.410.46)
[실시예 3] 화합물 3의 제조[Example 3] Preparation of Compound 3
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA (0.5mL, 3.76mmol), 메틸클로로아세테이트 (1.88mmol) 및 KI (0.38g, 3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=6:2:22 v:v:v, Rf =0.67)로 정제시켜 화합물 3를 수득하였다(흰색 액상, 74mg, 12% yield).The hono kiol (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.88mmol), TEA (0.5mL, 3.76mmol), methyl chloroacetate (1.88mmol) and KI (0.38g, 3.76mmol) And reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.67) 3 (white liquid, 74 mg, 12% yield).
1H NMR (CDCl3, 400MHz) δ 3.41(m, 4H), 3.81(s, 3H), 4.70(s, 2H), 5.08(m, 5H), 5.98(m, 2H), 6.80(d, J=8.1Hz, 1H), 6.88(d, J=8.2Hz, 1H), 7.00(s, 1H), 7.04(d, J=8.2Hz, 1H), 7.24 (m, 3H); 13C NMR (CDCl3, 100MHz) δ 34, 39, 52, 65, 111, 115.5, 115.6, 116, 127.6, 127.9, 128, 130.2, 130.4, 131, 132, 136, 137, 150, 155, 169; ESI-MS: m/z [M+Na]+361.2(calcd.338.4) 1 H NMR (CDCl 3, 400MHz ) δ 3.41 (m, 4H), 3.81 (s, 3H), 4.70 (s, 2H), 5.08 (m, 5H), 5.98 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 7.00 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 7.24 (m, 3H); 13 C NMR (CDCl 3 , 100 MHz) 隆 34, 39, 52, 65, 111, 115.5, 115.6, 116, 127.6, 127.9, 128, 130.2, 130.4, 131, 132, 136, 137, 150, 155, 169; ESI-MS: m / z [M + Na] < + > 361.2 (calcd.338.4)
[실시예 4] 화합물 4의 제조[Example 4] Preparation of Compound 4
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA(0.5mL, 3.76mmol), 벤질-2-브로모아세테이트 (1.88mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=6:2:22 v:v:v, Rf =0.7)로 정제시켜 화합물 4를 수득하였다(흰색 액상, 100mg, 9% yield).Hono kiol (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.88mmol), TEA (0.5mL, 3.76mmol), benzyl 2-bromoacetate (1.88mmol) and KI (3.76mmol) And the reaction was allowed to proceed at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.7) to obtain Compound 4 (white liquid, 100 mg, 9% yield).
1H NMR (CDCl3, 400MHz) δ 3.35(d, J=6.7Hz, 2H), 3.45(d, J=6.6Hz, 2H), 4.57(s, 2H), 4.68(s, 2H), 5.05(m, 4H), 5.17(s, 2H), 5.23(s, 2H), 5.97(m, 2H), 6.68(d, J=8.6Hz, 1H), 6.77(d, J=8.3Hz, 1H), 7.02(dd, J=2.0Hz, 8.3Hz, 1H), 7.11(ds, J=2.0Hz, 1H), 7.32(m, 12H) 1 H NMR (CDCl 3, 400MHz ) δ 3.35 (d, J = 6.7Hz, 2H), 3.45 (d, J = 6.6Hz, 2H), 4.57 (s, 2H), 4.68 (s, 2H), 5.05 ( J = 8.6 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1 H), 5.17 (s, 2H) 7.02 (dd, J = 2.0 Hz, 8.3 Hz, 1H), 7.11 (ds, J = 2.0 Hz, 1H), 7.32
[실시예 5] 화합물 5의 제조[Example 5] Preparation of Compound 5
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA(3.76mmol), 벤질-2-브로모아세테이트 (1.88mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=6:2:22 v:v:v, Rf =0.5)로 정제시켜 화합물 5를 수득하였다(흰색 액상, 30mg, 4% yield). Hono kiol (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.88mmol), was added TEA (3.76mmol), benzyl 2-bromoacetate (1.88mmol) and KI (3.76mmol) at room temperature For 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.5) to give compound 5 (white liquid, 30 mg, 4% yield).
[실시예 6] 화합물 6의 제조[Example 6] Preparation of Compound 6
화합물 2 (100mg, 0.38mmol)을 MeOH에 용해시킨 후 KOH(2.2mmol)을 넣고 상온에서 밤새도록 반응시켰다. 반응 완결 확인(전개용매 EA에서 Rf값 = 0.3)후, 약염기/DCM으로 워-컵하고 여과하여 화합물 6를 수득하였다(60mg, 75% yield).Compound 2 (100 mg, 0.38 mmol) was dissolved in MeOH, and KOH (2.2 mmol) was added thereto, followed by reaction at room temperature overnight. After confirmation of the completion of the reaction (R f value = 0.3 in developing solvent EA), the reaction mixture was war -coupled with weak base / DCM and filtered to give compound 6 (60 mg, 75% yield).
1H NMR (CDCl3, 400MHz) δ 1.28(s, 2H), 3.40(d, J=6.8Hz, 2H), 3.52(d, J=6.4Hz, 2H), 4.59(s, 2H), 4.75(s, 2H), 5.12(m, 4H), 6.02(m, 2H), 6.85(d, J=9.6Hz, 1H), 6.87(d, J=8.4Hz, 1H), 7.13(dd, J=2Hz, 8Hz, 1H), 7.17(ds, J=2Hz, 1H), 7.38(ds, J=2Hz, 1H), 7.42(dd, J=2Hz, 8Hz, 1H); ESI-MS: m/z [M+Na]+405.2(calcd.382.41) 1 H NMR (CDCl 3, 400MHz ) δ 1.28 (s, 2H), 3.40 (d, J = 6.8Hz, 2H), 3.52 (d, J = 6.4Hz, 2H), 4.59 (s, 2H), 4.75 ( J = 8.4 Hz, 1H), 7.13 (dd, J = 2 Hz, 2H), 5.12 (m, 4H), 6.02 , 8 Hz, 1H), 7.17 (ds, J = 2 Hz, 1H), 7.38 (ds, J = 2 Hz, 1H), 7.42 (dd, J = 2 Hz, 8 Hz, 1H); ESI-MS: m / z [M + Na] < + > 405.2 (calcd.382.41)
[실시예 7] 화합물 7의 제조[Example 7] Preparation of Compound 7
화합물 1 (0.2g, 0.75mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA( 3.76mmol), 메틸클로로아세테이트 (1.88mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(EA:HEX=1:9 v:v)로 정제시켜 화합물 7를 수득하였다(흰색 액상, 206mg, 89% yield).Compound 1 (0.2 g, 0.75 mmol) was dissolved in acetone and Cs 2 CO 3 (0.88 mmol), TEA (3.76 mmol), methyl chloroacetate (1.88 mmol) and KI (3.76 mmol) Lt; / RTI > After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 1: 9 v: v) 7 (white liquid, 206 mg, 89% yield).
1H NMR (CDCl3, 400MHz) δ 3.36(d, J=6.4Hz, 2H), 3.50(d, J=6.8Hz, 2H), 3.78(s, 3H), 3.81(s, 3H), 4.68(s, 2H), 5.05(d, J=9.6Hz, 2H), 5.11(m, 2H), 6.02(m, 2H), 6.76(d, J=9.2Hz, 1H), 6.89(d, J=8.8Hz, 1H), 7.10(m, 2H), 7.32(m, 2H); 13CNMR(CDCl3, 100MHz) δ 34, 39, 52, 55, 65, 111.1, 111.4, 115.5, 115.6, 128.1, 128.3, 128.8, 130, 131.4, 132, 132.3, 136, 137, 154.7, 154.9, 169.5; ESI-MS: m/z [M+H]+353.2(calcd.352.42) 1 H NMR (CDCl 3, 400MHz ) δ 3.36 (d, J = 6.4Hz, 2H), 3.50 (d, J = 6.8Hz, 2H), 3.78 (s, 3H), 3.81 (s, 3H), 4.68 ( (m, 2H), 6.76 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1 H), 7.10 (m, 2 H), 7.32 (m, 2 H); 13 CNMR (CDCl 3 , 100 MHz)? 34, 39, 52, 55, 65, 111.1, 111.4, 115.5, 115.6, 128.1, 128.3, 128.8, 130, 131.4, 132, 132.3, 136, 137, 154.7, 154.9, 169.5 ; ESI-MS: m / z [M + H] < + > 353.2 (calcd. 352.42)
[실시예 8] 화합물 8의 제조[Example 8] Preparation of Compound 8
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA (3.76 mmol), 메틸클로로아세테이트 (1.88 mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=6:2:22 v:v:v, Rf =0.52)로 정제시켜 화합물 8를 수득하였다(흰색 액상, 74 mg, 12% yield).Hono kiol (0.5g, 1.88mmol) was dissolved in acetone, Cs 2 CO 3 (0.88mmol), TEA (3.76 mmol), was added methyl chloroacetate (1.88 mmol) and KI (3.76mmol) at room temperature for 24 hours Lt; / RTI > After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.52) 8 (white liquid, 74 mg, 12% yield).
1H NMR (CDCl3, 400MHz) δ 3.35(d, J=6.8Hz, 2H), 3.45(d, J=6.4Hz, 2H), 3.76(s, 3H), 4.55(s, 2H), 5.17(m, 5H), 5.99(m, 2H), 6.79(d, J=8.4Hz, 1H), 6.84(d, J=8.4Hz, 1H), 7.05(dd, J=2Hz, 10.4Hz, 1H), 7.13(ds, J=2Hz, 10.4Hz, 1H), 7.35(s, 1H), 7.38(dd, J=2.4Hz, 8.4Hz, 1H); ESI-MS: m/z [M+Na]+361.2(calcd.338.4) 1 H NMR (CDCl 3, 400MHz ) δ 3.35 (d, J = 6.8Hz, 2H), 3.45 (d, J = 6.4Hz, 2H), 3.76 (s, 3H), 4.55 (s, 2H), 5.17 ( J = 8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 2 Hz, 10.4 Hz, 1H) 7.13 (ds, J = 2 Hz, 10.4 Hz, 1H), 7.35 (s, 1H), 7.38 (dd, J = 2.4 Hz, 8.4 Hz, 1H); ESI-MS: m / z [M + Na] < + > 361.2 (calcd.338.4)
[실시예 9] 화합물 9의 제조[Example 9] Preparation of Compound 9
화합물 A (0.2g, 0.75mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.88mmol), TEA (3.76mmol), 메틸클로로아세테이트 (1.88mmol) 및 KI (3.76mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(EA:HEX=1:9 v:v)로 정제시켜 화합물 9를 수득하였다(흰색 액상, 206mg, 89% yield).Compound A (0.2 g, 0.75 mmol) was dissolved in acetone and Cs 2 CO 3 (0.88 mmol), TEA (3.76 mmol), methyl chloroacetate (1.88 mmol) and KI (3.76 mmol) Lt; / RTI > After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (EA: HEX = 1: 9 v: v) to give compound 9 (white liquid, 206 mg, 89% yield).
1H NMR (CDCl3, 400MHz) δ 3.36(d, J=6.8Hz, 2H), 3.42(d, J=6.8Hz, 2H), 3.76(s, 3H), 3.86(s, 3H), 4.54(s, 2H), 5.05(m, 3H), 5.11(m, 1H), 6.00(m, 2H), 6.81(d, J=8.4Hz, 1H), 6.90(d, J=2.4Hz, 1H), 7.05(dd, J=2Hz, 8.4Hz, 1H), 7.14(ds, J=2.4Hz, 1H), 7.38(ds, J=2.4Hz, 1H), 7.46(dd, J=2Hz, 8.4Hz, 1H); 13CNMR(CDCl3, 100MHz) δ 34, 39, 52, 55, 66, 110, 113, 115.3, 115.7, 127, 128.1, 128.4, 130, 131, 131.1, 131.3, 133, 137, 137.5, 153, 156, 169; ESI-MS: m/z [M+Na]+375.1(calcd.352.42) 1 H NMR (CDCl 3, 400MHz ) δ 3.36 (d, J = 6.8Hz, 2H), 3.42 (d, J = 6.8Hz, 2H), 3.76 (s, 3H), 3.86 (s, 3H), 4.54 ( (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H) (Dd, J = 2 Hz, 8.4 Hz, 1H), 7.14 (ds, J = 2.4 Hz, 1H), 7.38 ); 13 CNMR (CDCl 3 , 100 MHz) 隆 34, 39, 52, 55, 66, 110, 113, 115.3, 115.7, 127, 128.1, 128.4, 130, 131, 131.1, 131.3, 133, 137, 137.5, 153, 156 , 169; ESI-MS: m / z [M + Na] < + > 375.1 (calcd. 352.42)
[실시예 10] 화합물 10의 제조[Example 10] Preparation of Compound 10
호노키올 (0.2g, 0.75mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.15mmol), 에틸클로로아세테이트 (1.5mmol) 및 KI (0.015mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(EA:HEX=1:3 v:v)로 정제시켜 화합물 10를 수득하였다(노란색 액상, 90mg, 27% yield).Cs 2 CO 3 (0.15 mmol), ethyl chloroacetate (1.5 mmol) and KI (0.015 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 1: 3 v: v) 10 (yellow liquid phase, 90 mg, 27% yield).
1H NMR (CDCl3, 400MHz) δ 1.27(t, 3H), 1.31(t, 3H), 3.36(d, J=6.4Hz, 2H), 3.51(d, J=6.8Hz, 2H), 4.25(q, 2H), 4.25(q, 2H), 4.53(s, 2H), 4.66(s, 2H), 5.07(q, 2H), 5.07(q, 2H), 6.01(m, 1H), 6.01(m, 1H), 6.78(d, J=10.8Hz, 1H), 6.80(d, J=10.8Hz, 1H), 7.05(dd, J=2Hz, 8Hz, 1H), 7.43(m, 2H) 1 H NMR (CDCl 3, 400MHz ) δ 1.27 (t, 3H), 1.31 (t, 3H), 3.36 (d, J = 6.4Hz, 2H), 3.51 (d, J = 6.8Hz, 2H), 4.25 ( 2H), 5.07 (q, 2H), 6.01 (q, 2H), 4.53 (s, 2H), 4.66 2H), 7.48 (m, 2H), 6.78 (d, J = 10.8 Hz,
[실시예 11] 화합물 11의 제조[Example 11] Preparation of Compound 11
호노키올 (0.2g, 0.75mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.15mmol), 2-클로로-N-메틸아세트아미드 (1.5mmol) 및 KI (0.015mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(EA:HEX=2:1 v:v)로 정제시켜 화합물 11를 수득하였다(노란색 액상, 169mg, 55% yield).Cs 2 CO 3 (0.15 mmol), 2-chloro-N-methylacetamide (1.5 mmol) and KI (0.015 mmol) were added to the reaction mixture and the mixture was stirred at room temperature for 24 hours Lt; / RTI > After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 2: 1 v: v) 11 (yellow liquid, 169 mg, 55% yield).
1H NMR (CDCl3, 400MHz) δ 2.76(ds, J=4.8Hz, 3H), 2.92(ds, J=5.2Hz, 3H), 3.38(ds, J=6.8Hz, 2H), 3.49(ds, J=6Hz, 2H), 4.44(s, 2H), 5.11(m, 4H), 6.02(m, 2H), 6.31(s, 1H), 6.63(s, 1H), 6.86(d, J=8.8Hz, 1H), 6.89(d, J=8.8Hz, 1H), 7.13(s, 1H), 7.24(m, 1H), 7.35(s, 1H) 1 H NMR (CDCl 3, 400MHz ) δ 2.76 (ds, J = 4.8Hz, 3H), 2.92 (ds, J = 5.2Hz, 3H), 3.38 (ds, J = 6.8Hz, 2H), 3.49 (ds, 1H), 6.63 (s, 1H), 6.86 (d, J = 8.8Hz, 2H) 1H), 7.29 (m, IH), 7.35 (s, IH)
[실시예 12] 화합물 12의 제조[Example 12] Preparation of Compound 12
호노키올 (0.2g, 0.75mmol)을 아세톤에 용해시킨 후 Cs2CO3 (0.15mmol), 2-클로로아세트아미드 (1.5mmol) 및 KI (0.015mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(EA:HEX=4:1 v:v)로 정제시켜 화합물 12를 수득하였다(흰색 액상, 196mg, 33% yield).Cs 2 CO 3 (0.15 mmol), 2-chloroacetamide (1.5 mmol) and KI (0.015 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 4: 1 v: v) to obtain Compound 12 (white liquid, 196 mg, 33% yield).
1H NMR (DMSO, 400MHz) δ 3.34(ds, J=6.8Hz, 2H), 3.45(ds, J=6.8Hz, 2H), 4.37(s, 2H), 4.48(s, 2H), 5.03(d, J=10Hz, 2H), 5.09(d, J=16.8Hz, 2H), 5.97(m, 2H), 6.91(d, J=8.4Hz, 1H), 6.92(d, J=8.8Hz, 1H), 7.03(s, 1H), 7.09(s, 1H), 7.10(s, 1H), 7.34(s, 1H), 7.37(ds, J=2.4Hz, 1H), 7.39(ds, J=2Hz, 1H), 7.41(s, 1H), 7.45(s, 1H) 1 H NMR (DMSO, 400MHz) δ 3.34 (ds, J = 6.8Hz, 2H), 3.45 (ds, J = 6.8Hz, 2H), 4.37 (s, 2H), 4.48 (s, 2H), 5.03 (d (D, J = 8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H) , 7.39 (s, IH), 7.09 (s, IH), 7.10 (s, IH), 7.34 ), 7.41 (s, 1 H), 7.45 (s, 1 H)
[실시예 13] 화합물 13의 제조[Example 13] Preparation of Compound 13
호노키올 (0.5g, 1.88mmol)을 아세톤에 용해시킨 후 Cs2CO3 (2.8mmol) 및 브로모아세토니트릴 (1.8mmol)를 가하고 상온에서 24시간동안 반응시켰다. 반응이 완료되면 감압농축하여 용매를 제거하고, 물과 DCM를 이용하여 워-컵한 후, 수득된 유기층을 무수 MgSO4로 건조시킨 후 여과 및 감압 농축하였다. 얻어진 잔사를 실리카 컬럼 크로마토그래피(DCM:Ether:HEX=49:2:49 v:v:v)로 정제시켜 화합물 13를 수득하였다(노란색 액상, 397mg, 61% yield).(0.5 g, 1.88 mmol) was dissolved in acetone, Cs 2 CO 3 (2.8 mmol) and bromoacetonitrile (1.8 mmol) were added and reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The organic layer was washed with water and DCM, and the organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (DCM: Ether: HEX = 49: 2: 49 v: v: v) 13 (yellow liquid phase, 397 mg, 61% yield).
1H NMR (DMSO, 400MHz) δ 3.37(ds, J=6.8Hz, 2H), 3.43(ds, J=6.4Hz, 2H), 4.59(s, 2H), 4.79(s, 2H), 5.09(m, 4H), 5.96(m, 2H), 6.96(d, J=8.4Hz, 1H), 7.00(d, J=9.2Hz, 1H), 7.14(m, 2H), 7.34(m, 2H) 1 H NMR (DMSO, 400MHz) δ 3.37 (ds, J = 6.8Hz, 2H), 3.43 (ds, J = 6.4Hz, 2H), 4.59 (s, 2H), 4.79 (s, 2H), 5.09 (m (D, J = 9.2 Hz, 1H), 7.14 (m, 2H), 7.34 (m, 2H)
[[ 실험예Experimental Example 1] One] 아세틸콜린에스테라제Acetylcholinesterase (( AChEAChE ) 및 ) And 부티릴콜린에스테라제Butyrylcholinesterase (( BuChEBuChE ) 저해 시험() Inhibition test ( In vitroIn vitro assay) assay)
상기 실시예에서 제조된 O-치환된 호노키올 유도체 화합물에 대하여, AChE 및 BuChE 억제 활성을 문헌[Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone, R.M. Biochem. Pharmacol. 1961, 7, 88-95]에 보고된 비색 측정 방법에 의해 30 ℃에서 평가하였다. With respect to the O-substituted monovalent chroman derivative compounds prepared in the above examples, AChE and BuChE inhibitory activities were measured according to Ellman, G. L .; Courtney, K. D .; Andres, B .; Featherstone, R.M. Biochem. Pharmacol. 1961, 7, 88-95).
AChE 억제 활성용 분석 용액은 0.1M 포스페이트 완충액(pH 8), 0.3 mM 5,5'-디티오-비스(2-니트로벤조산)(DTNB, 엘만 시약), 0.02 단위의 AChE(Sigma Chemical Co., 소 적혈구로부터), 및 효소 반응의 기질로서 0.5 mM 아세틸티오콜린 요오다이드로 이루어졌다. 상기 시험 화합물을 상기 분석 용액에 가하고 30℃에서 5 분 동안 상기 효소와 예비 배양하였다. 상기 기간 후에, 상기 기질을 가하였다. 412 nm에서의 흡광도 변화를 미세플레이트 판독기 디지스캔(Digiscan) 340T를 사용하여 5 분간 기록하고, 반응 속도를 비교하고, 시험 화합물의 존재로 인한 억제%를 계산하였다. 상기 반응 속도는 최소한 3 회 측정치를 사용하여 계산하였으며, 시험 화합물의 존재로 인한 억제%는 상기 화합물이 없는 대조군에 대해 계산하였다. 50%의 AChE 억제를 생성시키는 화합물 농도(IC50)를 측정하였다. 그 결과를 하기 표 1에 나타내었다.The analytical solution for AChE inhibition activity was prepared by adding 0.1 M phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis (2-nitrobenzoic acid) (DTNB, Ellman's reagent), 0.02 units of AChE (Sigma Chemical Co., From bovine erythrocytes), and 0.5 mM acetylthiocholine iodide as a substrate for the enzymatic reaction. The test compound was added to the assay solution and pre-incubated with the enzyme at 30 ° C for 5 minutes. After the period, the substrate was added. Absorbance changes at 412 nm were recorded for 5 minutes using a microplate reader Digiscan 340T, the rate of reaction was compared and the% inhibition due to the presence of the test compound was calculated. The rate of the reaction was calculated using at least three measurements, and the percent inhibition due to the presence of the test compound was calculated for the control without the compound. Compound concentration (IC 50 ) producing 50% AChE inhibition was measured. The results are shown in Table 1 below.
BuChE 억제 활성용 분석 용액은 인간 혈청으로부터의 부티릴콜린에스테라제 0.01 단위, 0.1M 나트륨 포스페이트 완충액(pH 8), 0.3 mM 5,5'-디티오-비스(2-니트로벤조산)(DTNB, 엘만 시약), 및 효소 반응의 기질로서 0.5 mM 부티릴티오콜린 요오다이드로 이루어졌다. 효소 활성을, 412 nm에서의 흡광도를 미세플레이트 판독기 디지스캔 340T를 사용하여 5 분간 측정함으로써 측정하였다. 시험 화합물을 30 ℃에서 10 분 동안 상기 효소와 예비 배양하였다. 상기 반응 속도는 최소한 3 회 측정치를 사용하여 계산하였다. IC50은 억제제가 없는 경우에 대해 효소 활성을 50% 감소시키는 각 화합물의 농도로서 정의된다. 그 결과를 하기 표 1에 나타내었다. The assay solution for BuChE inhibitory activity contained 0.01 units of butyrylcholinesterase from human serum, 0.1M sodium phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis (2-nitrobenzoic acid) (DTNB, Ellman's reagent) and 0.5 mM butyrylthiocholine iodide as a substrate for the enzyme reaction. Enzyme activity was measured by measuring absorbance at 412 nm for 5 minutes using a microplate reader DIGISCAN 340T. The test compound was pre-incubated with the enzyme at 30 ° C for 10 minutes. The reaction rate was calculated using at least three measurements. IC 50 is defined as the concentration of each compound that reduces the enzyme activity by 50% in the absence of inhibitor. The results are shown in Table 1 below.
상기 표 1에 나타낸 바와 같이, 상기 실시예에서 제조된 O-치환된 호노키올 유도체 화합물들은 콜린에스터라제(ChEs) 저해 활성을 나타내었다.As shown in Table 1, the O-substituted monovalent choline derivative compounds prepared in the above Example exhibited cholinesterase (ChEs) inhibitory activity.
특히, 화합물 1의 경우 호노키올의 2번 위치에 메틸기가 치환된 구조로, 아세틸콜린에스터라제(AChE)만을 선택적으로 저해함과 동시에 호노키올의 4번 위치에 메틸기가 치환된 4-O-메틸호노키올에 비해 매우 우수한 AChE 저해 활성을 나타내었다. Particularly, Compound 1 has a structure in which the methyl group is substituted at the 2-position of the honokiol, and the 4-O- AChE inhibitory activity was superior to that of methylnonochiol.
또한, 화합물 2, 3 및 8 내지 12의 경우 호노키올의 2번 또는 4번 위치에 적어도 하나의 메톡시카보닐메틸기, 에톡시카보닐메틸기, 메틸아미노카보닐메틸기 또는 아미노카보닐메틸기가 치환된 구조로, 부티릴콜린에스테라제(BuChE)만을 선택적으로 저해함과 동시에 4-O-메틸호노키올과 대비하여 현저하게 향상된 강력한 BuChE 저해활성을 나타내었다. Further, in the case of compounds 2, 3 and 8 to 12, at least one of the methoxycarbonylmethyl group, the ethoxycarbonylmethyl group, the methylaminocarbonylmethyl group or the aminocarbonylmethyl group is substituted in the 2- or 4-position of the honokiol Structure selectively inhibited butyrylcholinesterase (BuChE) and exhibited remarkably enhanced strong BuChE inhibitory activity as compared to 4-O-methylhornokiol.
따라서, 본 발명의 O-치환된 호노키올 유도체 화합물은 아세틸콜린에스터라제(AChE) 저해 활성 또는 부티릴콜린에스테라제(BuChE) 저해 활성을 가지고 있으므로, 퇴행성 질환의 예방 또는 치료용 약제학적 조성물 및 퇴행성 질환의 예방 또는 개선용 건강보조식품 조성물의 유효성분으로 매우 유용하게 사용될 수 있다.Accordingly, the O-substituted monovalent choline derivative of the present invention has an acetylcholinesterase (AChE) inhibitory activity or a butyrylcholinesterase (BuChE) inhibitory activity, so that the pharmaceutical composition for preventing or treating degenerative diseases And as an active ingredient of a health supplement food composition for preventing or ameliorating a degenerative disease.
Claims (8)
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 서로 독립적으로 수소, C1-C7알킬, 시아노C1-C7알킬 또는 -(CH2)mCOR3이고;
R3는 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR4R5이고;
m은 1 내지 5의 정수이고;
R4 및 R5는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이고;
단, R1과 R2가 동시에 수소 또는 C1-C7알킬인 경우 및 R1이 수소이고 R2가 C1-C7알킬인 경우는 제외된다.An O-substituted monovalent choline derivative compound represented by the following formula (1).
[Chemical Formula 1]
In Formula 1,
R 1 and R 2 are independently of each other hydrogen, C 1 -C 7 alkyl, cyano C 1 -C 7 alkyl or - (CH 2 ) m COR 3 ;
R 3 is C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 4 R 5 ;
m is an integer from 1 to 5;
R 4 and R 5 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;
Provided that when R 1 and R 2 are simultaneously hydrogen or C 1 -C 7 alkyl and R 1 is hydrogen and R 2 is C 1 -C 7 alkyl,
상기 R1이 C1-C7알킬이고 R2가 수소인 O-치환된 호노키올 유도체 화합물.The method according to claim 1,
Wherein said R < 1 > is C1-C7 alkyl and R < 2 > is hydrogen.
상기 R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고, R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고, R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴인 O-치환된 호노키올 유도체 화합물.The method according to claim 1,
One of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 , R 6 and R 7 are each independently C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, and C6-C12 aryl C1-C7 alkyloxy, hydroxy or -NR 8 R 9, R 8 and R 9 are each independently hydrogen, C1-C7-alkyl or C6-C12 aryl substituted with O- hono kiol Derivatives.
상기 O-치환된 호노키올 유도체 화합물은 하기 구조로부터 선택되는 O-치환된 호노키올 유도체 화합물.
The method according to claim 1,
The O-substituted monovalent choline derivative compound is selected from the following structures.
상기 퇴행성 질환은 파킨슨 병 또는 알츠하이머 병인 약제학적 조성물.6. The method of claim 5,
Wherein said degenerative disease is Parkinson's disease or Alzheimer's disease.
[화학식 2]
상기 화학식 2에서,
R1 및 R2 중 하나는 -CH2COR6이고, 나머지 하나는 수소, C1-C7알킬 또는 -CH2COR7이고;
R6 및 R7은 각각 독립적으로 C1-C7알콕시, C6-C12아릴옥시, C6-C12아릴C1-C7알킬옥시, 히드록시 또는 -NR8R9이고;
R8 및 R9는 각각 독립적으로 수소, C1-C7알킬 또는 C6-C12아릴이다.A composition for the selective inhibitory activity of butyrylcholinesterase containing an O-substituted monovalent cholinergic derivative represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient.
(2)
In Formula 2,
One of R 1 and R 2 is -CH 2 COR 6 and the other is hydrogen, C 1 -C 7 alkyl or -CH 2 COR 7 ;
R 6 and R 7 are each independently C 1 -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR 8 R 9 ;
R 8 and R 9 are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020170165983A KR102001381B1 (en) | 2017-12-05 | 2017-12-05 | Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020170165983A KR102001381B1 (en) | 2017-12-05 | 2017-12-05 | Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20190066342A true KR20190066342A (en) | 2019-06-13 |
KR102001381B1 KR102001381B1 (en) | 2019-07-18 |
Family
ID=66847867
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020170165983A KR102001381B1 (en) | 2017-12-05 | 2017-12-05 | Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102001381B1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113024404A (en) * | 2021-03-10 | 2021-06-25 | 郑州大学 | Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof |
KR20220069889A (en) | 2022-05-10 | 2022-05-27 | 빛나매크로주식회사 | Waste livestock treatment device with a waste heat recovery type deodorizer |
CN115215771A (en) * | 2022-08-06 | 2022-10-21 | 蚌埠医学院 | Honokiol derivative, preparation method and application in preparation of antitumor drugs |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080104760A1 (en) | 2006-09-14 | 2008-05-08 | Rawls-Meehan Martin B | Methods and systems of an adjustable bed |
KR20090094916A (en) | 2008-03-04 | 2009-09-09 | 주식회사 바이오랜드 | Composition comprising an extract of Magnolia officinalis Rehd. et Wils. or 4-O-methylhonokiol for preventing baldness and promoting hair growth |
KR100926466B1 (en) | 2008-09-25 | 2009-11-13 | 주식회사 바이오랜드 | A pharmaceutical composition for treating or preventing amyloidosis diseases comprising 4-o-methylhonokiol |
KR100932962B1 (en) | 2008-09-25 | 2009-12-21 | 주식회사 바이오랜드 | A functional food composition for improving and preventing amyloid-related diseases comprising 4-o-methylhonokiol |
-
2017
- 2017-12-05 KR KR1020170165983A patent/KR102001381B1/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080104760A1 (en) | 2006-09-14 | 2008-05-08 | Rawls-Meehan Martin B | Methods and systems of an adjustable bed |
KR20090094916A (en) | 2008-03-04 | 2009-09-09 | 주식회사 바이오랜드 | Composition comprising an extract of Magnolia officinalis Rehd. et Wils. or 4-O-methylhonokiol for preventing baldness and promoting hair growth |
KR100926466B1 (en) | 2008-09-25 | 2009-11-13 | 주식회사 바이오랜드 | A pharmaceutical composition for treating or preventing amyloidosis diseases comprising 4-o-methylhonokiol |
KR100932962B1 (en) | 2008-09-25 | 2009-12-21 | 주식회사 바이오랜드 | A functional food composition for improving and preventing amyloid-related diseases comprising 4-o-methylhonokiol |
Non-Patent Citations (3)
Title |
---|
Bioorganic & Medicinal Chemistry Letters, Vol.14, pp.2621-2625 (2004)* * |
Chemistry & Biology, Vol.18, pp.1053-1064 (2011)* * |
J. Med. Chem., Vol.54, pp.6469-6481 (2011)* * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113024404A (en) * | 2021-03-10 | 2021-06-25 | 郑州大学 | Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof |
CN113024404B (en) * | 2021-03-10 | 2024-05-24 | 郑州大学 | Quaternary amine salt type honokiol/magnolol derivative and preparation method and application thereof |
KR20220069889A (en) | 2022-05-10 | 2022-05-27 | 빛나매크로주식회사 | Waste livestock treatment device with a waste heat recovery type deodorizer |
CN115215771A (en) * | 2022-08-06 | 2022-10-21 | 蚌埠医学院 | Honokiol derivative, preparation method and application in preparation of antitumor drugs |
CN115215771B (en) * | 2022-08-06 | 2024-04-02 | 蚌埠医学院 | Honokiol derivative, preparation method and application thereof in preparation of antitumor drugs |
Also Published As
Publication number | Publication date |
---|---|
KR102001381B1 (en) | 2019-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jiang et al. | Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease | |
KR102001381B1 (en) | Novel o-substituted honokiol derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient | |
KR20140147619A (en) | Novel chalcone derivatives and the use thereof | |
EP2857007B1 (en) | Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease | |
EP2327402B1 (en) | Composition containing 4-o-methylhonokiol for treating or preventing amyloid- related diseases | |
KR101511056B1 (en) | Novel S-allyl cysteine derivatives and their biological functions | |
EP3831821A1 (en) | Compound for treating nervous system diseases and use thereof | |
KR102290603B1 (en) | Novel lipoic acid-heterocycle thioacetal compounds and uses of the same | |
KR102233120B1 (en) | Novel paeonol-tryptamine compounds and their biological applications | |
KR102677119B1 (en) | Novel cannabidiol derivative, process for preparing the same and composition for improving cognitive function comprising the same | |
KR102255957B1 (en) | Novel dibenzooxaphosphinine oxide derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient | |
US20100227851A1 (en) | Method of preventing and/or treating a neurodegenerative disease by administering an extract of Lycoris chejuensis and/or a compound isolated therefrom | |
KR20120053245A (en) | Composition for anti-cancer effect comprising gallic acid derivatives | |
JP2022522299A (en) | Pharmaceutical composition for the prevention or treatment of nervous system diseases | |
KR101667215B1 (en) | Novel tryptamine conjugated compounds and their biological applications | |
KR101548927B1 (en) | Novel lipoic acid-4-amino piperidine conjugated compounds and uses of the same | |
CN110698411B (en) | 4- (aminoalkyl) phthalazine-1-ketone compound, preparation method and application thereof | |
US10464901B2 (en) | Composition including benzene diamine derivative for preventing or treating degenerative brain diseases | |
CN110003034B (en) | Hydroxyflurbiprofen Mannich base compounds, and preparation method and application thereof | |
JP6605760B2 (en) | Novel compound that promotes osteoblast differentiation and suppresses adipocyte differentiation, production method thereof and application thereof | |
CN105111195A (en) | Tacrine-bifendate heterocomplex as well as preparation method and application thereof | |
RU2819611C1 (en) | 7-hydroxycoumarin derivative for inducing mitophagy in cells, method for production and use thereof | |
KR101881689B1 (en) | A Novel Synthetic Method of Glifolin derivative and Pharmaceutical Composition for Treatment and Prevention of Hyperlipidemia Comprising the Same as an Active Ingredient | |
KR101932473B1 (en) | Novel honokiol triazole conjugated compounds and pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient | |
KR20120047503A (en) | Calcone derivatives having apoptosis-inducing activation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right |