CN103936577A - Preparation method of E-3,4-dihydroxyphenylvinyl ketone and application thereof as nerve protection drug - Google Patents
Preparation method of E-3,4-dihydroxyphenylvinyl ketone and application thereof as nerve protection drug Download PDFInfo
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- CN103936577A CN103936577A CN201310017347.2A CN201310017347A CN103936577A CN 103936577 A CN103936577 A CN 103936577A CN 201310017347 A CN201310017347 A CN 201310017347A CN 103936577 A CN103936577 A CN 103936577A
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- Prior art keywords
- substituted
- pent
- dihydroxyphenyl
- diacetoxyphenyl
- compound
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- 239000003814 drug Substances 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 34
- 210000005036 nerve Anatomy 0.000 title abstract description 3
- MOPYIPOZUDHBJM-IJIVKGSJSA-N (1e,4e)-1,5-bis(3,4-dihydroxyphenyl)penta-1,4-dien-3-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)\C=C\C1=CC=C(O)C(O)=C1 MOPYIPOZUDHBJM-IJIVKGSJSA-N 0.000 title description 3
- -1 E-3,4-dihydroxyphenylvinyl ketone compound Chemical class 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- 230000000324 neuroprotective effect Effects 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- DGMYRPFYNFQCHM-UHFFFAOYSA-N 5-phenylpentan-2-one Chemical class CC(=O)CCCC1=CC=CC=C1 DGMYRPFYNFQCHM-UHFFFAOYSA-N 0.000 claims description 7
- PCYGLFXKCBFGPC-UHFFFAOYSA-N 3,4-Dihydroxy hydroxymethyl benzene Natural products OCC1=CC=C(O)C(O)=C1 PCYGLFXKCBFGPC-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 claims description 6
- BKOOGPJYPVGVMG-PKNBQFBNSA-N (e)-1-(3,4-dihydroxyphenyl)-6-phenylhex-1-en-3-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)CCCC1=CC=CC=C1 BKOOGPJYPVGVMG-PKNBQFBNSA-N 0.000 claims description 5
- LSDCSRVRGXXTPZ-UHFFFAOYSA-N 8-phenyloctan-2-one Chemical class CC(=O)CCCCCCC1=CC=CC=C1 LSDCSRVRGXXTPZ-UHFFFAOYSA-N 0.000 claims description 5
- RPLPLVTUNDLQFY-ACCUITESSA-N [2-acetyloxy-4-[(e)-3-oxo-6-phenylhex-1-enyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1\C=C\C(=O)CCCC1=CC=CC=C1 RPLPLVTUNDLQFY-ACCUITESSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- HNJNJAMBNUZQDM-QHHAFSJGSA-N (e)-1-(3,4-dihydroxyphenyl)-5-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one Chemical compound C1=C(O)C(OC)=CC(CCC(=O)\C=C\C=2C=C(O)C(O)=CC=2)=C1 HNJNJAMBNUZQDM-QHHAFSJGSA-N 0.000 claims description 4
- LOEMUCWNSZVSGY-JXMROGBWSA-N (e)-1-(3,4-dihydroxyphenyl)-5-phenylpent-1-en-3-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)CCC1=CC=CC=C1 LOEMUCWNSZVSGY-JXMROGBWSA-N 0.000 claims description 4
- OFYMOMSYSRJHNT-VMPITWQZSA-N (e)-5-(3-chlorophenyl)-1-(3,4-dihydroxyphenyl)pent-1-en-3-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)CCC1=CC=CC(Cl)=C1 OFYMOMSYSRJHNT-VMPITWQZSA-N 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- FBRSQWXDGGEUSX-FMIVXFBMSA-N [2-acetyloxy-4-[(e)-3-oxo-5-phenylpent-1-enyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1\C=C\C(=O)CCC1=CC=CC=C1 FBRSQWXDGGEUSX-FMIVXFBMSA-N 0.000 claims description 4
- QWPKSGMKZMSMBL-UXBLZVDNSA-N [2-acetyloxy-4-[(e)-5-(3,4-dimethoxyphenyl)-3-oxopent-1-enyl]phenyl] acetate Chemical compound C1=C(OC)C(OC)=CC=C1CCC(=O)\C=C\C1=CC=C(OC(C)=O)C(OC(C)=O)=C1 QWPKSGMKZMSMBL-UXBLZVDNSA-N 0.000 claims description 4
- MBDJVHLTCCERMJ-JXMROGBWSA-N [2-acetyloxy-4-[(e)-5-(3-chlorophenyl)-3-oxopent-1-enyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1\C=C\C(=O)CCC1=CC=CC(Cl)=C1 MBDJVHLTCCERMJ-JXMROGBWSA-N 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000004090 neuroprotective agent Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical class O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims description 3
- LPXLSRPTQKGMGD-ZRDIBKRKSA-N (e)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)CCCCC1=CC=CC=C1 LPXLSRPTQKGMGD-ZRDIBKRKSA-N 0.000 claims description 3
- 102000014461 Ataxins Human genes 0.000 claims description 3
- 108010078286 Ataxins Proteins 0.000 claims description 3
- 206010008025 Cerebellar ataxia Diseases 0.000 claims description 3
- 206010008027 Cerebellar atrophy Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000032319 Primary lateral sclerosis Diseases 0.000 claims description 3
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 3
- 206010046298 Upper motor neurone lesion Diseases 0.000 claims description 3
- RWGNJWYVGXCPEE-WYMLVPIESA-N [2-acetyloxy-4-[(e)-3-oxo-7-phenylhept-1-enyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1\C=C\C(=O)CCCCC1=CC=CC=C1 RWGNJWYVGXCPEE-WYMLVPIESA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 claims description 3
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 claims description 3
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Chemical class O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 3
- 201000010901 lateral sclerosis Diseases 0.000 claims description 3
- 230000000670 limiting effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 208000005264 motor neuron disease Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 229940100595 phenylacetaldehyde Drugs 0.000 claims description 3
- 150000004714 phosphonium salts Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 3
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical group C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- XMGMFRIEKMMMSU-UHFFFAOYSA-N phenylmethylbenzene Chemical group C=1C=CC=CC=1[C]C1=CC=CC=C1 XMGMFRIEKMMMSU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 229910000510 noble metal Inorganic materials 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 abstract description 6
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 239000000376 reactant Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 15
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 description 15
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
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- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 7
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- 238000010828 elution Methods 0.000 description 7
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- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 5
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- 230000009385 viral infection Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
The invention relates to a E-3,4-dihydroxyphenylvinyl ketone compound I having a formula represented in the description and an application thereof in preparation of nerve protection drugs or drug compositions for treating neurodegenerative diseases; wherein definitions of each group in the formula are listed in the description. The invention also relates to a preparation method of the compound.
Description
Technical Field
The patent relates to the application of E-3, 4-dihydroxystyryl ketone compounds in preparing neuroprotective drugs for neurodegenerative diseases, and also relates to a preparation method of the compounds.
Background
Neurodegenerative diseases are a class of chronic, progressive neurological diseases. The diseases mainly comprise Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cerebellar atrophy, different types of spinocerebellar ataxia, spinal muscular atrophy, primary lateral sclerosis and the like. In recent years, the number of neurodegenerative diseases is increasing, for example, the prevalence rate of Alzheimer disease in China is 2% -5%, and the prevalence rate of new diseases is 1% every year. Neurodegenerative diseases have been found to be caused by a variety of different causes, including insufficient nutrition provided by neurons or glial cells, excessive glutamate receptor activity, excessive reactive oxygen levels, decreased mitochondrial energy production, inflammation, viral infections, and nuclear or mitochondrial DNA mutations that interact with each other, ultimately leading to neurological dysfunction and cell death. Due to the complex and various action mechanisms, no effective mature method and medicament for preventing and treating the disease exist so far. There is therefore a need to find highly effective and multi-targeted drugs for the treatment of such diseases.
Caffeic Acid Phenethyl Ester (CAPE), a natural product extracted from natural propolis, has various biological activities, such as anti-tumor, anti-oxidation, anti-inflammatory, antibacterial, anti-atherosclerosis and anti-HIV-1 integrase, etc. (Chen Y., Wang S., et al, anti-cancer drugs.2001, 12(2), 143-149). Recently, it was discovered that caffeic acid phenethyl ester can exert neuroprotective effects by blocking neurodegenerative damage (Wei X, Ma Z., Fontanlla CV., et al. neuroscience.2008, 155(4), 1098-1105). Since caffeic acid phenethyl ester is not easy to permeate blood brain barrier and has high metabolism speed in vivo (NicolaC., Luana K., et al. journal of agricultural and Food chemistry.2007, 55, 3398-3407), neuroprotective activity is limited to a certain extent. The inventor designs a novel compound by taking caffeic acid phenethyl ester as a lead compound according to a biological electron isostere principle, a hydrogen bond action theory and the like, so that the blood brain barrier is easier to pass through, the stability is stronger, and the neuroprotective activity is greatly improved.
Disclosure of Invention
The invention aims to provide application of E-3, 4-dihydroxystyryl ketone compounds in medicines for treating neurodegenerative diseases and a preparation method of the compounds.
Aiming at the defects that caffeic acid phenethyl ester is not easy to permeate a blood brain barrier and has high metabolism speed in vivo, the caffeic acid phenethyl ester is structurally modified, so that a new compound is easier to permeate the blood brain barrier, and the stability is stronger, thereby improving the neuroprotective activity. The ester group is improved to a ketone group because the ketone group can reduce the metabolic rate and enhance the stability; the selective protection of phenolic hydroxyl can increase fat solubility, thereby enhancing the capability of penetrating the blood brain barrier.
The inventor discovers that the compound shown in the general formula I can realize neuroprotective effect through the evaluation of activity of scavenging free radicals, the evaluation of model for inhibiting generation of nitric oxide and the like through the evaluation of in vitro antioxidant capacity and the evaluation of neuroprotective activity at a cellular level, and the protective effect of the compound is obviously stronger than that of lead compound Caffeic Acid Phenethyl Ester (CAPE). The compound shown in the general formula I can be used for drugs with neuroprotective effect, and can be used for treating Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, multiple sclerosis, cerebellar atrophy, different types of spinocerebellar ataxia, spinal muscular atrophy, cerebral ischemia, primary lateral sclerosis and the like.
According to one embodiment of the invention, the invention relates to derivatives of general formula I:
general formula I
Specific compounds within the compounds of formula I: e-1- (3, 4-dihydroxyphenyl) -5-phenyl-pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3, 4-dihydroxyphenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3-methoxy-4-hydroxyphenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3, 4-dimethoxyphenyl-pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -6-phenylhex-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -7-phenyl-hept-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5-phenyl-pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-diacetoxyphenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3-methoxy-4-acetoxyphenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-dimethoxyphenyl) -pent-1-en-3-one, e-1- (3, 4-diacetoxyphenyl) -6-phenylhex-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -7-phenyl-hept-1-en-3-one.
The compounds of formula I according to the invention can be prepared according to the following synthetic routes, which will help to understand the invention by the following reaction schemes, without limiting the content of the invention.
Wherein,
r is H, or is optionally substituted with 1-4 substituents selected from bromo, chloro, fluoro, iodo, or 1-4 carbon saturated alkyl, unsaturated alkyl, halo-substituted alkyl, alkoxy, alkoxyacyl, alkenyloxy, aryloxy, carboxy, amino, hydroxy, cyano, mercapto, or nitro;
r' is H or a hydroxyl protecting group, which generally refers to a functional group having a function of protecting a hydroxyl group in one or more steps of a reaction, and may be selected from the group consisting of substituted formyl, substituted acetyl, substituted propionyl, substituted butyryl, substituted benzoyl, substituted phenylacetyl, substituted phenylpropionyl, substituted phenylbutyryl, substituted carbamoyl, p-toluenesulfonyl, pivaloyl, chloroacetyl, trichloroacetyl, bromoacetyl, methyl, methoxymethyl, benzyloxymethyl, 2- (trimethylsilyl) ethoxymethyl, methylthiomethyl, phenylthiomethyl, azidomethyl, cyanomethyl, 2-dichloro-1, 1-difluoroethyl, tetrahydropyranyl, 1-ethoxyethyl, benzoylmethyl, cyclopropylmethyl, propargyl, isopropyl, cyclohexyl, tert-butyl, benzyl, trimethylsilyl, tert-butyl, benzyl, and the like, Tert-butyl dimethoxy silyl, tert-butyl diphenyl silyl, triisopropyl silyl, methylene acetal, diphenylmethylene ketal, dimethylmethylene ketal, cyclohexylidene ketal;
n is 1-5 saturated or unsaturated carbon chains.
In the above synthetic route, when n is 2 or 4, substituted benzaldehyde or cinnamaldehyde is used as a raw material, and is reacted with acetone under the catalysis of alkali to generate alpha, beta-unsaturated substituted phenethyl (butyl) methyl ketone 1a-1e (1g), then saturated substituted phenethyl (butyl) methyl ketone 2a-2e (2g) is generated under the catalytic hydrogenation of 10% Pd/C, and is reacted with 3, 4-dihydroxybenzaldehyde under the catalysis of pyrrolidine to generate trans-alpha, beta-unsaturated ketone 3a-3e (3g) with phenolic hydroxyl, and finally, pyridine is used as a catalyst to be reacted with acid anhydride or acid chloride to generate trans-target product 4a-4e (4g) with protected phenolic hydroxyl; when n is 3, chloropropone is used as a starting material, firstly, the chloropropone reacts with triphenylphosphine under the condition of heating reflux to generate phosphonium salt, then a 10% sodium carbonate aqueous solution is used for processing to obtain a Wittig reagent, the Wittig reagent and phenylacetaldehyde undergo a Wittig reaction to obtain alpha, beta-unsaturated phenylpropyl methyl ketone 1f, then saturated substituted phenylpropyl methyl ketone 2f is generated under the catalytic hydrogenation of 10% Pd/C, then the saturated substituted phenylpropyl methyl ketone reacts with 3, 4-dihydroxybenzaldehyde under the catalysis of pyrrolidine to generate trans-alpha, beta-unsaturated ketone 3f with phenolic hydroxyl, and finally, pyridine is used as a catalyst and reacts with anhydride or acyl chloride to generate a protected trans-target product 4f with the phenolic hydroxyl.
In another aspect, the present invention is directed to a pharmaceutical composition comprising at least one compound of formula I or an optical isomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
Pharmaceutical compositions of the compounds of the present invention may be administered by any of the following means: oral, aerosol inhalation, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intracardiac, intrasternal or intravenous administration. The pharmaceutical composition of the present invention can be administered alone or in combination with other neuroprotective agents. The animals to be treated include mammals, reptiles, crustaceans, amphibians, fish, and poultry. The main range is mammals, in particular humans.
When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. The carrier used in the tablet can comprise filler, lubricant, disintegrant and binder. Fillers may include, but are not limited to, starch, pregelatinized starch, dextrin, powdered sugar, lactose, mannitol, microcrystalline cellulose. Lubricants include, but are not limited to, stearic acid, calcium stearate, magnesium stearate, talc, oxidized vegetable oils, polyethylene glycol, sodium lauryl sulfate, aerosil, talc. Disintegrants may include, but are not limited to, croscarmellose sodium, crospovidone, starch and its derivatives, low substituted hydroxypropyl cellulose, effervescent disintegrants. Binders may include, but are not limited to, hydroxypropyl cellulose, povidone, starch slurry, dextrin, sugar powder, syrup, mucilage, cellulose, and derivatives thereof. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspoemulsion formulations are prepared by combining the active ingredient with suitable suspending agents which may include, but are not limited to, wetting agents, flocculating agents, and deflocculating agents. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When the compound is used locally, particularly for treating affected surfaces or organs which are easy to reach by local external application, such as glasses, skin or lower intestinal nerve diseases, the compound can be prepared into different local preparation forms according to different affected surfaces or organs, and the specific description is as follows:
when administered topically to the eye, the compounds of the invention may be formulated as a micronized suspension or solution in sterile saline at a pH that is isotonic, with or without the addition of preservatives such as benzylalkenoxides. For ophthalmic use, the compounds may also be formulated in the form of a paste such as petrolatum.
When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, self petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or sterile injectable solutions. Among the carriers or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
It is further noted that the dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition of the patient, the strength of the activity of the compound, time of administration, rate of metabolism, and the severity of the condition, and the particular dosage and method of administration will be determined by the attending physician according to the particular condition of the patient.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention. In the following examples, "spin-drying the solvent under reduced pressure" refers to "evaporating the solvent by a rotary evaporator under reduced pressure with a water pump" in general, unless otherwise specified.
Example 1:
preparation of 1-phenylbut-1-en-3-one (Compound 1a)
After 5ml of acetone was added to 5ml of 10% NaOH aqueous solution, acetone solution (10ml) of benzaldehyde (5.30g, 0.05mol) was slowly added dropwise, the reaction temperature was controlled not to exceed 30 ℃ and the reaction was continued for 3 hours after about 1 hour, and the reaction was completed by TLC detection. The reaction mixture was neutralized with 10% HCl to PH 7, the solvent was dried under reduced pressure, extracted with ethyl acetate, and the ester layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was dried by spin-drying under reduced pressure, and separated and purified by silica gel column (petroleum ether/ethyl acetate elution) to obtain the objective compound 1a as pale yellow crystals 6.0g, in 82.5% yield. m.p.39-41 ℃.1HNMR(400MHz，CDCl3)δ：7.46(d，.J＝16.2Hz，1H，C2-H)，7.14-7.30(m，5H，Ar-H)，6.61(d，J＝16.2Hz，1H，C1-H)，2.30(s，3H，CH3)
Preparation of 1- (3-chlorophenyl) -but-1-en-3-one (Compound 1b)
To 55ml of 1M K2CO3After 40ml of acetone is added into the aqueous solution, slowly dropping 3-chlorobenzaldehyde (7.05g, 50mmol) in acetone (10ml), controlling the reaction temperature not to exceed 30 ℃, continuing the reaction overnight after dropping for about 1h, and detecting the reaction by TLC. The reaction mixture was neutralized with 10% HCl to PH 7, the solvent was dried under reduced pressure, extracted with ethyl acetate, and the ester layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was dried under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate elution) to obtain the objective compound 1b as a yellow liquid 8.0g in 88.3% yield.
Preparation of 1- (3, 4-dihydroxyphenyl) -but-1-en-3-one (Compound 1c)
Dissolving 3, 4-dihydroxy benzaldehyde (1.38g, 10mmol) in a mixed solvent of acetone (15ml) and acetonitrile (30ml), adding a catalytic amount of pyrrolidine and acetic acid, adding a molecular sieve, heating and refluxing for 3h in the dark, cooling, performing reduced pressure spin-drying on the solvent, and separating and purifying by using a silica gel column (petroleum ether/ethyl acetate elution) to obtain a target product 1c with the yield of 55.3 percent and the m.p.173-174 ℃.
Preparation of 1- (3-methoxy-4-hydroxyphenyl) -but-1-en-3-one (Compound 1d)
Using the synthesis procedure as described above for compound 1a, with 3-methoxy-4-hydroxybenzaldehyde as the reactant, compound 1d was obtained as a yellow solid 4.20g, 83.7% yield, m.p.133-134 ℃.
1- (3, 4-Dimethoxyphenyl) -but-1-en-3-one (Compound 1e)
Using the synthesis procedure of compound 1a as above, with 3, 4-dimethoxybenzaldehyde as the reactant, white cotton-like solid 1e was obtained in 70.6% yield, m.p.85-86 ℃.
5-phenylpent-3-en-2-one (Compound 1f)
Dropwise adding a chloroform solution of chloropropanone (6.5g, 70.3mmol) into a chloroform solution of triphenylphosphine (20g, 76.3mmol), heating and refluxing for 50min, cooling, dropwise adding into 600ml of anhydrous ether, separating out a white solid, filtering, drying to obtain a white solid, then adding the white solid into a 10% sodium carbonate solution, stirring overnight, and filtering the reaction solution to obtain the triphenylphosphine. Triphenylphosphine (1.03g, 2.5mmol) and phenylacetaldehyde (300mg, 2.5mmol) were dissolved in THF and stirred at room temperature for 6h, TLC check complete reaction. And (3) performing rotary drying on the solvent under reduced pressure, adding a small amount of water, extracting by ethyl acetate, combining ester layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, performing rotary drying on the solvent under reduced pressure, and performing separation and purification (petroleum ether/ethyl acetate elution) by using a silica gel column to obtain a colorless liquid 1f of the target compound, wherein the total yield is 50.4%.
1-Phenylhex-1, 3-dien-5-one (Compound 1g)
Using the synthesis method of compound 1a as above, with cinnamaldehyde as the reactant, 1g of a white solid was obtained in a yield of 76.3%, m.p.67-69 ℃.
Example 2:
preparation of 4-phenylbutan-2-one (Compound 2a)
1a (0.29g, 2.0mmol) was dissolved in dichloromethane (10ml), 10% Pb/C (30mg) was added, the reaction was carried out for 12 hours under a hydrogen atmosphere, TLC was performed to detect completion of the reaction, filtration was carried out with Celite, the filtrate was dried under reduced pressure, and separation and purification (petroleum ether/ethyl acetate elution) were carried out with a silica gel column to obtain the objective compound as colorless liquid 2a in a yield of 90.0%.
Preparation of 4- (3-chlorophenyl) -butan-2-one (2b)
Using the synthesis procedure described above for compound 2a, with 1- (3-chlorophenyl) -but-1-en-3-one as the reactant, 2b was obtained in 89.3% yield.
Preparation of 4- (3, 4-dihydroxyphenyl) -butan-2-one (2c)
Using the above synthesis of compound 2a, with 1- (3, 4-dihydroxyphenyl) -but-1-en-3-one as the reactant, 2c was obtained in 85.7% yield, m.p.85-86 ℃.
Preparation of 4- (3-methoxy-4-hydroxyphenyl) -butan-2-one (2d)
Using the above synthesis of compound 2a, 1- (3-methoxy-4-hydroxyphenyl) -but-1-en-3-one as the reactant gave 2d in 88.6% yield.
Preparation of 4- (3, 4-Dimethoxyphenyl) -butan-2-one (2e)
Using the synthesis procedure described above for compound 2a, with 1- (3, 4-dimethoxyphenyl) -but-1-en-3-one as the reactant, 2e was obtained in 92.4% yield, m.p.54-56 ℃.
Preparation of 5-phenylpent-2-one (2f)
Using the above synthesis of compound 2a, 5-phenylpent-3-ene 2-one as the reactant gave 2f as a colorless liquid in 90.0% yield.
Preparation of 6-phenylhex-2-one (2g)
Using the above synthesis method of compound 2a, 1-phenylhex-1, 3-dien-5-one as a reactant, 2g of a colorless liquid was obtained in a yield of 93.2%.
Example 3:
preparation of E-1- (3, 4-dihydroxyphenyl) -5-phenyl-pent-1-en-3-one (3a)
Adding 4-phenylbutan-2-one (0.45g and 3mmol) and catalytic amount of pyrrolidine and acetic acid into tetrahydrofuran (30ml) solvent, stirring, slowly dropwise adding 3, 4-dihydroxybenzaldehyde (0.38g and 3mmol) in tetrahydrofuran (20ml), stirring at room temperature for 1h, keeping away from light, detecting by TLC, drying the solvent under reduced pressure, adding a small amount of water, extracting with ethyl acetate, combining ester layers, washing with saturated sodium chloride solution and saturated sodium bisulfite solution, drying with anhydrous sodium sulfate, drying the solvent under reduced pressure, and separating and purifying with silica gel column (petroleum ether/ethyl acetate elution) to obtain the target compound, namely yellow solid 3a, 0.37g, yield 55.5% and m.p.153-155 ℃.1HNMR(400MHz，DMSO-d6)δ：9.37(s，2H，2×OH)，7.49(d，J＝16.2Hz，1H，C2-H)，6.75-7.84(m，8H，Ar-H)，6.53(d，J＝16.2Hz，1H，C1-H)，2.98(t，J＝15.0Hz，2H，CH2CO)，2.86(t，J＝15.0Hz，2H，CH2)
Preparation of E-1- (3, 4-dihydroxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one (3b)
Using the synthesis procedure as described above for compound 3a, with 4- (3-chlorophenyl) -butan-2-one as the reactant, yellow solid 3b was obtained in 63.1% yield, m.p.127-129 ℃.1HNMR(400MHz，DMSO-d6)δ：9.40(s，2H，2×OH)，7.49(d，J＝16.2Hz，1H，C2-H)，6.76-7.35(m，7H，Ar-H)，6.58(d，J＝16.2Hz，1H，C1-H)，3.00(t，J＝13.2Hz，2H，CH2CO)，2.87(t，J＝13.2Hz，2H，CH2).13CNMR(100MHz，DMSO-d6)δ：198.6，148.5，145.6，144.1，143.2，132.9，130.1，128.3，127.2，125.8，122.9，121.7，115.8，114.8，30.7，29.7，29.2.HR-MS(ESI+)m/z：303.07825[M+H]+.Found：303.07831[M+H]+
Preparation of E-1- (3, 4-dihydroxyphenyl) -5- (3, 4-dihydroxyphenyl) -pent-1-en-3-one (3c)
Using the above synthetic method of Compound 3a, with 4- (3, 4-dihydroxyphenyl)) -butan-2-one as a reactant gave 3c as a yellow solid in 56.8% yield, m.p.148-150 ℃.1HNMR(400MHz，DMSO-d6)δ：9.59(s，1H，OH)，9.14(s，1H，OH)，8.64(s，2H，2×OH)，7.44(d，J＝16.2Hz，1H，C2-H)，6.45-7.06(m，6H，Ar-H)，6.56(d，J＝16.2Hz，1H，C1-H)，2.87(t，J＝14.7Hz，2H，CH2CO)，2.67(t，J＝14.7Hz，2H，CH2).13CNMR(100MHz，DMSO-d6)δ：199.4，148.9，146.0，145.4，143.7，143.3，132.6，126.3，123.5，122.1，119.3，116.2，115.8，155.3，42.1，29.6.HR-MS(ESI+)m/z：301.10705[M+H]+.，Found：301.10701[M+H]+
Preparation of E-1- (3, 4-dihydroxyphenyl) -5- (3-methoxy-4-hydroxyphenyl) -pent-1-en-3-one (3d)
Using the synthesis of compound 3a above, with 4- (3-methoxy-4-hydroxyphenyl) -butan-2-one as the reactant, yellow solid 3d was obtained in 67.4% yield, m.p.197-198 ℃.1HNMR(400MHz，DMSO-d6)δ：9.03(s，3H，3×OH)，7.46(d，J＝15.6Hz，1H，C2-H)，6.64-7.84(m，6H，Ar-H)，6.61(d，J＝15.6Hz，1H，C1-H)，3.74(s，3H，OMe)，2.93(t，J＝14.7Hz，2H，CH2CO)，2.76(t，J＝14.7Hz，2H，CH2).13CNMR(100MHz，DMSO-d6)δ：199.1，148.5，147.4，145.6，144.6，143.0，132.1，125.9，123.1，121.7，120.4，115.8，115.3，114.8，112.6，55.6，41.7，29.5.MS(ESI+)：[M+H]+m/z315，0，[M+Na]+m/z337.0.
Preparation of E-1- (3, -dihydroxyphenyl) -5- (3, 4-dimethoxyphenyl) -pent-1-en-3-one (3E)
Using the synthesis procedure described above for compound 3a, with 4- (3, 4-dimethoxyphenyl) butan-2-one as the reactant, white solid 3e was obtained in 58.0% yield, m.p.152-154 ℃.1HNMR(400MHz，DMSO-d6)δ：9.35(s，2H，2×OH)，7.45(d，J＝15.9Hz，1H，C2-H)，6.72-7.30(m，6H，Ar-H)，6.57(d，J＝15.9Hz，1H，C1-H)，4.04(s，3H，CH2CH2-p-Ar-OMe)，4.02(s，3H，CH2CH2-m-Ar-OMe)，2.95(t，J＝15.0Hz，2H，CH2CO)，2.81(t，J＝15.0Hz，2H，CH2).13CNMR(100MHz，DMSO-d6)δ：198.9，148.6，148.4，145.6，142.9，133.8，125.8，121.6，120.0，115.8，114.8，112.9，111.9，109.1，108.3，55.5，55.4，41.5，29.4
Preparation of E-1- (3, 4-dihydroxyphenyl) -6-phenylhex-1-en-3-one (3f)
Using the synthesis procedure of compound 3a above, with 5-phenylpentan-2-one as the reactant, white solid 3f was obtained in 55.3% yield, m.p.145-146 ℃.1HNMR(400MHz，DMSO-d6)δ：9.51(s，2H，2×OH)，7.42(d，J＝16.5Hz，1H，C2-H)，6.77-7.29(m，8H，Ar-H)，6.57(d，J＝16.5Hz，1H，C1-H)，2.59(m，4H，CH 2 CH2 CH 2)，1.83(m，2H，CH2 CH 2 CH2).13CNMR(100MHz，DMSO-d6)δ：199.9，148.9，146.0，143.2，142.3，128.8，126.3，126.2，123.5，122.0，116.2，115.3，35.0，26.3
Preparation of E-1- (3, 4-dihydroxyphenyl) -7-phenyl-hept-1-en-3-one (3g)
Using the synthesis procedure described above for compound 3a, using 6-phenylhex-2-one as the reactant, 3g of a pale yellow solid was obtained in 75.8% yield, m.p.109-111 ℃.1HNMR(400MHz，DMSO-d6)δ：9.36(s，2H，2×OH)，7.43(d，J＝15.9Hz，1H，C2-H)，6.75-7.30(m，8H，Ar-H)，6.54(d，J＝15.9Hz，1H，C1-H)，2.66(t，J＝12.9Hz，2H，CH2CO)，2.60(t， J＝12.9Hz，2H，CH 2 -Ar)，3.78(m，4H，CH2 CH 2 CH 2 CH2)
Example 4:
preparation of E-1- (3, 4-diacetoxyphenyl) -5-phenyl-pent-1-en-3-one (4a)
Dissolving compound 3a (0.18g, 0.67mmol) in acetic anhydride (3ml) solvent, adding anhydrous pyridine (0.11ml, 1.34mmol), stirring at room temperature for 5min, detecting reaction completion by TLC, dropping the reaction solution into ice water, extracting with ethyl acetate, combining ester layers, washing with saturated saline, drying with anhydrous sodium sulfate, separating and purifying with silica gel column (petroleum ether/ethyl acetate elution) to obtain white cotton-like solid 4a, 0.22mg, yield 92.5%, m.p.102-104 deg.C.1HNMR(400MHz，CDCl3)δ：7.47(d，J＝16.2Hz，1H，C2-H)，7.21-7.41(m，8H，Ar-H)，6.66(d，J＝16.2Hz，1H，C1-H)，2.99(s，4H，CH2CH2)，2.31(s，6H，2×OAc).13CNMR(100MHz，CDCl3)δ：198.9，168.2，168.0，143.6，142.4，141.0，140.7，133.3，128.5，128.4，126.9，126.6，126.1，124.0，122.8，86.0，42.7，30.0，20.6.HR-MS(ESI+)m/z：353.13835[M+H]+.Found：353.13883[M+H]+
Preparation of E-1- (3, 4-diacetoxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one (4b)
Using the synthesis procedure described above for compound 4a, with 1- (3, 4-dihydroxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one as the reactant, a pale pink solid 4b was obtained in 90.3% yield, m.p.77-78 ℃.1HNMR(400MHz，DMSO-d6)δ：7.63(d，J＝16.5Hz，1H，C2-H)，7.23-7.67(m，7H，Ar-H)，6.89(d，J＝16.5Hz，1H，C1-H)，3.03(t，J＝14.7Hz，2H，CH2CO)，2.87(t，J＝14.7Hz，2H，CH2)，2.28(s，6H，2×OAc).13CNMR(100MHz，DMSO-d6)δ：198.3，168.1，143.1，142.5，140.8，140.7，134.2，133.3，129.8，128.5，128.4，126.8，126.6，126.4，126.2，124.0，122.9，42.2，29.6，20.6.HR-MS(ESI+)m/z：387.09938[M+H]+.Found：387.10029[M+H]+
Preparation of E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-diacetoxyphenyl) -pent-1-en-3-one (4c)
Using the synthesis method of compound 4a as above, with 1- (3, 4-dihydroxyphenyl) -5- (3, 4-dihydroxyphenyl) -pent-1-en-3-one as the reactant, light yellow solid 4c was obtained in 95.2% yield, m.p.91-92 ℃.1HNMR(400MHz，CDCl3)δ：7.47(d，J＝16.2Hz，1H，C2-H)，7.06-7.42(m，6H，Ar-H)，6.65(d，J＝16.2Hz，1H，C1-H)，2.98(s，4H，CH2CH2)，2.31(s，3H，CH＝CH-p-Ar-OMe)，2.30(s，3H，CH＝CH-m-Ar-OMe)，2.29(s，3H，CH2CH2-p-Ar-OMe)，2.28(s，3H，CH2CH2-m-Ar-OMe).13CNMR(100MHz，CDCl3)δ：200.1，169.8，169.7，169.5，146.2，146.0，143.3，142.0，136.7，132.4，126.3，125.2，123.6，121.6，119.4，118.3，45.1，32.5，20.3，20.2，20.1.HR-MS(ESI+)m/z：469.14931[M+H]+.Found：469.14965[M+H]+，486.17679[M+NH3]+
Preparation of E-1- (3, 4-diacetoxyphenyl) -5- (3-methoxy-4-acetoxyphenyl) -pent-1-en-3-one (4d)
Using the synthesis of compound 4a as above, 1- (3, 4-dihydroxyphenyl) -5- (3-methoxy-4-hydroxyphenyl) -pent-1-en-3-one as the reactant gave 4d as a white solid in 91.9% yield, m.p.87-89 ℃.1HNMR(400MHz，CDCl3)δ：7.48(d，J＝16.2Hz，1H，C2-H)，6.78-7.43(m，6H，Ar-H)，6.67(d，J＝16.2Hz，1H，C1-H)，3.83(s，3H，OMe)，2.31(s，9H，3×OAc). 13CNMR(100MHz，CDCl3)δ：198.7，169.2，168.1，167.9，150.8，143.6，142.4，140.7，140.1，137.9，133.3，126.8，126.6，123.9，122.8，122.6，120.3，112.6，55.8，55.7，42.7，29.9，20.6.
Preparation of E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-dimethoxyphenyl) -pent-1-en-3-one (4E)
Using compounds 4a as aboveThe synthesis method uses 1- (3-dihydroxyphenyl) -5- (3, 4-dimethoxyphenyl) -pent-1-en-3-one as a reactant to obtain light yellow solid 4e, the yield is 92.2 percent, and the m.p.85-86 ℃.1HNMR(400MHz，CDCl3)δ：7.48(d，J＝15.9Hz，1H，C2-H)，6.76-7.41(m，6H，Ar-H)，6.67(d，J＝15.9Hz，1H，C1-H)，3.88(s，3H，CH2CH2-p-Ar-OMe)，3.86(s，3H，CH2CH2-m-Ar-OMe)，2.31(s，3H，2×OAc).13CNMR(100MHz，CDCl3)δ：199.0，167.9，147.3，143.6，142.4，140.6，133.6，126.9，126.6，123.9，122.8，120.1，111.7，111.2，61.8，55.9，55.8，42.9，30.9，29.7，20.6，
Preparation of E-1- (3, 4-diacetoxyphenyl) -6-phenylhex-1-en-3-one (4f)
Using the synthesis method of compound 4a as above, 1- (3, 4-dihydroxyphenyl) -6-phenylhex-1-en-3-one as a reactant gave 4f as a white solid in 91.5% yield, m.p.102-103 ℃.1HNMR(400MHz，CDCl3)δ：7.42(d，J＝16.5Hz，1H，C2-H)，7.20-7.41(m，8H，Ar-H)，6.64(d，J＝16.5Hz，1H，C1-H)，2.65(m，4H，CH 2CH2 CH 2)，2.31(s，6H，2×OAc)，2.01(m，2H，CH2 CH 2 CH2).13CNMR(100MHz，CDCl3)δ：199.7，168.1，143.5，142.4，141.5，140.4，133.4，128.5，126.9，125.9，123.9，122.8，40.2，35.1，25.6，20.6.HR-MS(ESI)m/z：367.15400[M+H].Found： 367.15465[M+H]+
Preparation of E-1- (3, 4-diacetoxyphenyl) -7-phenyl-hept-1-en-3-one (4g)
Using the synthesis method of compound 4a as above, using 1- (3, 4-dihydroxyphenyl) -7-phenyl-hept-1-en-3-one as a reactant, 4g of white solid was obtained in a yield of 90.5%, m.p.73-75 ℃.1HNMR(400MHz，CDCl3)δ：7.46(d，J＝16.5Hz，1H，C2-H)，7.17-7.40(m，8H，Ar-H)，6.65(d，J＝16.5Hz，1H，C1-H)，2.66(s，4H，CH 2 CH2CH2 CH 2 )，2.31(s，6H，2×OAc)，1.70(s，4H，CH2 CH 2 CH 2 CH2).13CNMR(100MHz，CDCl3)δ：199.8，168.0，167.9，143.5，142.4，142.1，140.3，133.4，128.3，128.3，126.9，126.6，125.7，123.9，122.7，40.9，35.7，30.9，30.9，23.8，20.6.HR-MS(ESI+)m/z：381.16965[M+H]+.Found：381.16999[M+H]+
Example 5:
evaluation of the ability of the synthesized compounds of the general formula I to scavenge free radicals in vitro (DPPH)
Principle of experiment
1, 1-diphenyl-2-picrylhydrazyl (DPPH)) is a stable nitrogen-centered radical, and when a radical scavenger is added to DPPH solution, its lone pair of electrons is paired, absorption disappears or decreases, resulting in a lighter solution color, and the degree of change is linear with the degree of radical scavenging.
Two experimental methods
Preparing DPPH into 0.1mM/L ethanol solution; and diluting the compound stock solution into ethanol solutions with different concentrations. And respectively putting 100 mu l of compound solutions with different concentrations into a 96-well plate, adding 100 mu l/well DPPH solution, shaking in the dark for 30min, and measuring the OD value at the wavelength of 517 nm. For each compound, 5-6 concentrations were set, each concentration was paralleled by 3-4 wells, and the experiment was repeated 3 times.
The radical scavenging rate of the compounds is shown in table 1.
Results of three experiments (see Table 1)
DPPH radical scavenging ratio (%)
As can be seen from the results in the table above, the compounds 3a-3g in the general formula I have obvious ability of scavenging free radicals, and the ability of scavenging free radicals is stronger than CAPE.
Example 6:
evaluation of NO-producing cell model inhibiting activity of synthesized compounds of general formula I
Principle of experiment
Microglia are immunologically active macrophage-like cells present in the central nervous system. Excessive activation of microglia leads to the secretion of a variety of biologically active factors, such as nitric oxide and inducible nitric oxide synthase, interleukins, interferons, tumor necrosis factor, colony stimulating factor, cyclooxygenase 2 and prostaglandins, and active oxygen, which have strong toxic effects on neurons. Lipopolysaccharide (LPS) can activate microglia to release toxic factors such as nitric oxide, and the release amount of nitric oxide can be detected by a nitric oxide detection kit. The cell model for inhibiting NO generation can be used for screening neuroprotective drugs.
Two experimental methods
(1) Cells were seeded in 96-well plates (3 x 10)4Cells/100 μ L), incubated for 1 day at 37 ℃, 5% CO2, and 95% air in an incubator;
(2) setting a blank control group, an LPS group and an administration group in each 96-well plate, respectively adding compound solutions with final concentrations of 2.5 mu M/L, 5 mu M/L, 10 mu M/L, 20 mu M/L and 40 mu M/L into the administration group, paralleling 8 wells in each concentration, and placing in an incubator for incubation for 3 h;
(3) respectively adding LPS solution with final concentration of 100nM/L into the LPS group and the administration group, and incubating in an incubator for 24 h;
(4) placing the supernatant in a new 96-well plate, adding the nitric oxide kit reagent, and placing for 5min at room temperature in a dark place;
(5) the OD value was measured at a wavelength of 540 nm.
Results of three experiments (see Table 2)
| Compound numbering | IC50Value (μ M/L) |
| CAPE | 6.41 |
| Ac-CAPE | 7.22 |
| 3a | 10.28 |
| 3b | 10.27 |
| 3d | 6.36 |
| 3e | 14.46 |
| 3f | 5.40 |
| 3g | 6.33 |
| 4a | 10.84 |
| 4b | 8.32 |
| 4d | 5.58 |
| 4e | 12.82 |
| 4f | 5.49 |
| 4g | 4.76 |
IC inhibition of NO production by Compounds of Table 250Value of
As can be seen from the results in the table above, the compounds 3a to 4g in the general formula I have stronger activity of inhibiting the generation of nitric oxide, wherein the activities of 3g, 4d, 4f and 4g are stronger than CAPE and Ac-CAPE (compounds in which two phenolic hydroxyl groups of CAPE are protected by acetyl).
As can be seen from examples 5 and 6, the compounds of the general formula I have neuroprotective effects such as scavenging free radicals and inhibiting the generation of nitric oxide, and part of the activity of the compounds is greater than that of Caffeic Acid Phenethyl Ester (CAPE).
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined by the scope of the appended claims.
Claims (8)
1. Compounds of the general formula I
General formula I
Wherein,
r is H, or is optionally substituted with 1 to 4 substituents selected from bromo, chloro, fluoro, iodo, or saturated alkyl of 1 to 4 carbons, unsaturated alkyl, haloalkyl, alkoxy, alkoxyacyl, alkenyloxy, aryloxy, carboxy, amino, hydroxy, cyano, mercapto, or nitro;
r' is H or a hydroxyl protecting group, which generally refers to a functional group having a function of protecting a hydroxyl group in one or more steps of a reaction, and may be selected from the group consisting of substituted formyl, substituted acetyl, substituted propionyl, substituted butyryl, substituted benzoyl, substituted phenylacetyl, substituted phenylpropionyl, substituted phenylbutyryl, substituted carbamoyl, p-toluenesulfonyl, pivaloyl, chloroacetyl, trichloroacetyl, bromoacetyl, methyl, methoxymethyl, benzyloxymethyl, 2- (trimethylsilyl) ethoxymethyl, methylthiomethyl, phenylthiomethyl, azidomethyl, cyanomethyl, 2-dichloro-1, 1-difluoroethyl, tetrahydropyranyl, 1-ethoxyethyl, benzoylmethyl, cyclopropylmethyl, propargyl, isopropyl, cyclohexyl, tert-butyl, benzyl, trimethylsilyl, tert-butyl, benzyl, and the like, Tert-butyl dimethoxy silyl, tert-butyl diphenyl silyl, triisopropyl silyl, methylene acetal, diphenylmethylene ketal, dimethylmethylene ketal, cyclohexylidene ketal;
n is 1-5 saturated or unsaturated carbon chains.
2. Compounds of the general formula I according to claim 1, which are in particular: e-1- (3, 4-dihydroxyphenyl) -5-phenyl-pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3, 4-dihydroxyphenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3-methoxy-4-hydroxyphenyl) -pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -5- (3, 4-dimethoxyphenyl-pent-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -6-phenylhex-1-en-3-one, E-1- (3, 4-dihydroxyphenyl) -7-phenyl-hept-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5-phenyl-pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3-chlorophenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-diacetoxyphenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3-methoxy-4-acetoxyphenyl) -pent-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -5- (3, 4-dimethoxyphenyl) -pent-1-en-3-one, e-1- (3, 4-diacetoxyphenyl) -6-phenylhex-1-en-3-one, E-1- (3, 4-diacetoxyphenyl) -7-phenyl-hept-1-en-3-one.
3. The synthesis of the compounds according to claims 1 and 2 can be prepared according to the following synthetic routes, which will help to understand the invention by the following reaction schemes, but without limiting the content of the invention;
4. the process according to claim 3, wherein when n is 2 or 4, substituted benzaldehyde or cinnamaldehyde is used as a raw material, and acetone is reacted under the catalysis of base to produce alpha, beta-unsaturated substituted phenethyl (butyl) methyl ketone 1a-1e (1g), then saturated substituted phenethyl (butyl) methyl ketone 2a-2e (2g) is produced through catalytic hydrogenation, and then the saturated substituted phenethyl (butyl) methyl ketone is reacted with 3, 4-dihydroxybenzaldehyde under the catalysis of catalyst to produce trans-alpha, beta-unsaturated ketone 3a-3e (3g) with phenolic hydroxyl, finally, base is used as a catalyst and acid anhydride or acid chloride is reacted to produce protected trans-target product 4a-4e (4 g); when n is 3, chloropropanone is used as a starting material, firstly, the chloropropanone reacts with triphenylphosphine under the condition of heating reflux to generate phosphonium salt, then alkali liquor is used for treating the phosphonium salt to obtain Wittig reagent, the Wittig reagent and phenylacetaldehyde are subjected to Wittig reaction to obtain alpha, beta-unsaturated phenylpropyl methyl ketone 1f, then, the saturated substituted phenylpropyl methyl ketone 2f is generated through catalytic hydrogenation reaction, and then, the substituted phenylpropyl methyl ketone reacts with 3, 4-dihydroxybenzaldehyde under the catalysis of a catalyst to generate trans-alpha, beta-unsaturated ketone 3f with phenolic hydroxyl, and finally, alkali is used as a catalyst to react with anhydride or acyl chloride to generate a trans-protected target product 4f with the phenolic hydroxyl.
5. The process according to claim 4, wherein the catalyst used for the catalytic hydrogenation is a noble metal catalyst containing Pt, Pd, Rh or Ru, preferably 10% Pd/C; condensation with 3, 4-dihydroxybenzaldehydesThe catalyst used in the synthesis reaction is weak acid and weak base or amino acid, preferably pyrrolidine and acetic acid; the catalyst used for the acylation reaction of the phenolic hydroxyl group is alkali, and pyridine is preferred; the alkali liquor used for synthesizing wittig reagent is preferably Na2CO3An aqueous solution.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and at least one pharmaceutically acceptable carrier.
7. Use of a compound according to claims 1-3 for the manufacture of a medicament as a neuroprotective agent.
8. The use of claim 7, wherein the neuroprotective drug is a drug for the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cerebellar atrophy, different types of spinocerebellar ataxia, spinal muscular atrophy, cerebral ischemia, primary lateral sclerosis.
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| CN105669418A (en) * | 2016-01-25 | 2016-06-15 | 西北农林科技大学 | Alpha, Beta-Unsaturated ketone compound and synthetic method thereof, and drug containing this compound and application thereof |
| WO2019080682A1 (en) * | 2017-10-25 | 2019-05-02 | 沈阳药科大学 | Method for synthesizing 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one |
| CN111792990A (en) * | 2019-04-09 | 2020-10-20 | 中国科学院上海药物研究所 | Unsaturated ketone compound, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105669418A (en) * | 2016-01-25 | 2016-06-15 | 西北农林科技大学 | Alpha, Beta-Unsaturated ketone compound and synthetic method thereof, and drug containing this compound and application thereof |
| CN105669418B (en) * | 2016-01-25 | 2019-03-01 | 西北农林科技大学 | Alpha, beta-unsaturated ketone compound and its synthetic method and drug and application containing the compound |
| WO2019080682A1 (en) * | 2017-10-25 | 2019-05-02 | 沈阳药科大学 | Method for synthesizing 1,7-di-(4-hydroxyphenyl)-heptane-1,4-dien-3-one |
| CN111792990A (en) * | 2019-04-09 | 2020-10-20 | 中国科学院上海药物研究所 | Unsaturated ketone compound, preparation method and application thereof |
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Application publication date: 20140723 |