CN106831799A - Hydroxy styrenes pyridine Mannich alkaloid compound, Preparation Method And The Use - Google Patents
Hydroxy styrenes pyridine Mannich alkaloid compound, Preparation Method And The Use Download PDFInfo
- Publication number
- CN106831799A CN106831799A CN201611181249.2A CN201611181249A CN106831799A CN 106831799 A CN106831799 A CN 106831799A CN 201611181249 A CN201611181249 A CN 201611181249A CN 106831799 A CN106831799 A CN 106831799A
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- CN
- China
- Prior art keywords
- acid
- pyridine
- compound
- hydroxy styrenes
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 106
- -1 alkaloid compound Chemical class 0.000 title claims abstract description 74
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229930013930 alkaloid Natural products 0.000 title claims abstract description 43
- XLLXMBCBJGATSP-UHFFFAOYSA-N 2-phenylethenol Chemical class OC=CC1=CC=CC=C1 XLLXMBCBJGATSP-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
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- 201000004810 Vascular dementia Diseases 0.000 claims abstract description 4
- 208000035475 disorder Diseases 0.000 claims abstract description 4
- 201000010901 lateral sclerosis Diseases 0.000 claims abstract description 4
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- 150000001875 compounds Chemical class 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
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- 239000002904 solvent Substances 0.000 claims description 27
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
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- 239000000126 substance Substances 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
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- 239000007864 aqueous solution Substances 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
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- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
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- 125000004970 halomethyl group Chemical group 0.000 claims description 3
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- 150000003222 pyridines Chemical class 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 150000005204 hydroxybenzenes Chemical class 0.000 claims description 2
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 2
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- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
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- 102100028661 Amine oxidase [flavin-containing] A Human genes 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
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- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
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- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- LXEKPEMOWBOYRF-UHFFFAOYSA-N [2-[(1-azaniumyl-1-imino-2-methylpropan-2-yl)diazenyl]-2-methylpropanimidoyl]azanium;dichloride Chemical compound Cl.Cl.NC(=N)C(C)(C)N=NC(C)(C)C(N)=N LXEKPEMOWBOYRF-UHFFFAOYSA-N 0.000 description 1
- HUGQNTGOVJKASF-UHFFFAOYSA-M [SH-].[I+] Chemical compound [SH-].[I+] HUGQNTGOVJKASF-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002555 anti-neurodegenerative effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- 125000005997 bromomethyl group Chemical group 0.000 description 1
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- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
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- 239000002329 esterase inhibitor Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052603 melanterite Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 239000003706 n methyl dextro aspartic acid receptor stimulating agent Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 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
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical class OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses the new hydroxy styrenes pyridine Mannich alkaloid compound of a class（I）And its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and the purposes in treatment and/or prevention nervus retrogression relevant disease medicine is prepared, including but not limited to nerve degenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to the hydroxy styrenes pyridine Mannich alkaloid compound that a class is new（I）
And its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition are related in preparation treatment and/or prevention nervus retrogression
Purposes in disease medicament, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV
The nervus retrogression diseases such as related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma
Disease.
Background technology
Alzheimer's disease（Alzheimer ' s disease, AD, senile dementia）Be one kind with progressive cognitive disorder
With the central nervous system degenerative disease based on memory infringement, its incidence of disease in ascendant trend year by year, as being only second to the heart
The frequently-occurring disease of angiosis and cancer, it is the 4th of the cause of death to be had gone up in developed countries such as America and Europes.According to world health
Organisation Report, global over-65s old man has 10% dysnoesia, wherein 1/2nd occur dull-witted, morbidity in more than 85 years old
Rate nearly 50%.In China AD patient numbers about 600-700 ten thousand, the incidence of disease is more than 5%.With adding for population in the world aging process
Hurry up, its incidence of disease is in obvious ascendant trend, is announced in December, 2013 according to Alzheimer's Disease International
's《The global implication of Alzheimer's disease：2013-2050》Pointed out in report, AD faces the coming few decades whole world is turned into most
Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value
It is up to surprising 1.35 hundred million.Due to AD clinical manifestations for memory capability, capacity of orientation, thinking and judgement go down, and
Activity of daily living reduction, or even there is abnormal Behavioral and psychological symptom etc., make patient care difficulty larger, to society and family's band
Carry out heavy burden.The medicine that current approved is used to treat light/moderate AD has acetylcholinesterase（AChE）Inhibitor, Yi Jiyong
In severe AD treatmentsN- methyl-D- aspartic acid（NMDA）Receptor antagonist, but Clinical practice shows that these medicines can pass through
The exitotoxicity of levels of acetylcholine or suppression excitatory amino acid in patient's body is improved to alleviate AD symptoms, but can not be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, poor appetite and
The serious toxic and side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically in the urgent need to research and development have new work
With the AD medicines of mechanism.
The disease that AD category many factors cause, pathogenesis is complicated, does not illustrate its pathogenesis, but research completely also so far
Show, the decline of patient's intracerebral levels of acetylcholine,βThe excessive generation of-amyloid is disorderly with deposition, metal ion metabolism
Disorderly, Ca2+Dysequilibrium,tauNeurofibrillary tangles, MAO-B caused by-protein hyperphosphorylation（MAO-B）Activity increases
By force, glutamate receptor activity is too high, oxidative stress produces a large amount of active oxygens（ROS）It is many with free radical and Neuroinflammation etc.
The factor of kind is played an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is using a traditional " medicine one
Target " drug design strategies, it was found that largely there is the medicine of high activity and high selectivity to a certain target spot, such as：Cholinesterase presses down
Preparation andN- methyl-D- aspartate receptor agonist etc., but these medicines are present that action target spot is single, Clinical practice is malicious secondary makees
With it is more, not good enough to the long-term efficacy of AD patient the problems such as.
In recent years, with constantly illustrating to AD pathogenesis, finding the occurrence and development of AD has many mechanism, multifactor
The characteristics of effect, the again interrelated network for influencing each other, constituting complexity during AD occurrence and development between different mechanisms
Regulator control system.Based on the above results, researcher proposes " Mutiple Targets targeted drug "（Multitarget-directed
Ligands, MTDLs）Strategy researches and develops anti-nerve degenerative diseases medicine.So-called " Mutiple Targets medicine " refers to that single chemistry is real
Body acts on the multiple target spots in disease network simultaneously, and the effect to each target spot can produce cooperative effect, makes gross effect more than each
Sum is answered in single-action, and such medicine is also referred to as " Multifunctional " or " Multipotential " medicine.Mutiple Targets medicine with it is many
Medicine use in conjunction and compound medicine are differred primarily in that：Dosage can be reduced, therapeutic effect is improved, is avoided between medicine
The toxic and side effect for interacting and thus bringing, homogeneous pharmacokinetic properties, be easy to use etc..Design and find tool simultaneously
There are acetylcholine esterase inhibition, the metal ion suppressed in MAO-B, anti-oxidation stress, selective complexation central tissues
（Particularly Cu2+And Fe2+）, and multiple biological activities Mutiple Targets AD medicines are current study hotspots more in a balanced way.Cause
This, research and development have novel chemical structure, new mechanism of action, and with Mutiple Targets（Or it is multi-functional）Effect, the secondary work of low toxicity
Anti- neurodegenerative disease therapeutic agent not only conforms with the active demand of social senilization's process, and with good city
Field prospect.
The content of the invention
The hydroxy styrenes pyridine Mannich alkaloid compound new present invention aim at a class is disclosed（I）And its pharmacy
Upper acceptable salt；
Another object of the present invention is to disclose such hydroxy styrenes pyridine Mannich alkaloid compound（I）And its can pharmaceutically connect
The preparation method of the salt received；
A further object of the present invention is open comprising such hydroxy styrenes pyridine Mannich alkaloid compound（I）And its pharmacy
The pharmaceutical composition of upper acceptable salt；
Still a further object of the present invention is to disclose such hydroxy styrenes pyridine Mannich alkaloid compound（I）And its can pharmaceutically connect
The salt received has multiple target effect, can be used to prepare the purposes in the medicine for the treatment of and/or prevention nervus retrogression relevant disease,
Including but not limited to vascular dementia, Alzheimer's, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple
The nerve degenerative diseases such as sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Hydroxy styrenes pyridine Mannich alkaloid compound disclosed in this invention（I）Chemical structure of general formula be：
In formula：R1And R2C is represented independently of one another1~C12Alkyl, benzyl, substituted benzyl, propargyl；NR1R2Also illustrate that tetrahydrochysene pyrrole
Base, morpholinyl, piperidyl, piperazinyl, 4- is coughed up by C1~C12Piperazinyl that alkyl is replaced, 4- by benzyl or substituted benzyl
The piperazinyl for being replaced ,-CH2NR1R2Can be in any possible position of phenyl ring with OH；Ar is expressed as follows shown（A）With（B）In
Any structure unit；
Above-mentioned term " substituted benzyl " refers to the benzyl replaced by the group that 1-4 is selected from the group on phenyl ring：F、Cl、Br、
I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substitution bases can be in phenyl ring
Any possible position.
Hydroxy styrenes pyridine Mannich alkaloid compound disclosed in this invention（I）And its pharmaceutically acceptable salt can
It is prepared by the following method and obtains：
In formula：R1、R2Definition and chemical structure of general formula with Ar（I）It is identical；-CH2NR1R2Can be arbitrarily possible in phenyl ring with OH
Position；X represents Cl or Br；R3Represent C1-C12Alkyl.
With 5- (halomethyl) -2,2,8- trimethyls -4H- [1,3] dioxane [4,5-c] pyridine compounds and their（1）To rise
Beginning raw material, it is solvent-free or under having solvent condition with phosphite ester（P(OR3)3）Reaction, obtains corresponding picolyl phosphoric acid easter class
Compound（2）；Gained compound（2）With hydroxy benzaldehyde compound under solvent and alkalescence condition（HO-PhCHO）Condensation, obtains
Isopropyl methene hydroxy styrenes pyridine compounds and their（3）；The compound that will be obtained（3）Isopropyl methene is removed in acidic aqueous solution
Protection group, obtains hydroxy styrenes pyridine compounds and their（4）；Finally, by compound（3）Or（4）In a solvent with formaldehyde, amine
Compound（HNR1R2）Reacted through Mannich, obtain final product hydroxy styrenes pyridine Mannich alkaloid compound（I）.
Its specific preparation method is described as follows：
Step a)：5- (halomethyl) -2,2,8- trimethyls -4H- [1,3] dioxane [4,5-c] pyridine compounds and their（1）In nothing
Solvent or have under solvent condition with phosphite ester（P(OR3)3）Reaction, obtains corresponding picolyl phosphoric acid easter class compound（2）；Its
In, reaction solvent for use is：N,N- dimethylformamide, dimethyl sulfoxide (DMSO), chlorobenzene, dichloro-benzenes, benzene,toluene,xylene or two
Phenylate；Compound（1）：The molar feed ratio of phosphite ester is 1.0：1.0 ~ 100.0, preferably molar feed ratio is 1.0：1.0~
20.0；Reaction temperature is 50 ~ 250 DEG C, and preferable reaction temperature is 100 ~ 160 DEG C；Reaction time is 30 minutes ~ 24 hours, preferably
Reaction time is 1 ~ 12 hour.
Step b)：The compound prepared by step a)（2）With hydroxy benzaldehyde class under solvent and alkalescence condition
Compound（HO-PhCHO）Condensation, obtains isopropyl methene hydroxy styrenes pyridine compounds and their（3）；Wherein, reaction solvent for use is：
C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N,N- dimethylformamide, dimethyl sulfoxide (DMSO),
Dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, preferred solvent is：Methyl alcohol, ethanol, isopropanol,N,N- dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane or toluene；Reacting alkali used is：Alkali metal hydroxide, alkali
Earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydride, C1-8It is the alkali metal salt of alcohol, organic
Tertiary amines or quaternary ammonium bases（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl morpholine,N- methyl piperidine, triethylene two
Amine, TBAH）, preferably alkali is：Potassium hydroxide, sodium hydride, potassium carbonate, triethylamine or sodium methoxide；Compound（2）：
Hydroxy benzaldehyde compound：The molar feed ratio of alkali is 1.0：0.9~5.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0：
1.0~3.0：1.0~6.0；Reaction temperature is -30 ~ 120 DEG C, and preferable reaction temperature is 0 ~ 100 DEG C；Reaction time is 1 ~ 24 hour,
Preferred reaction time is 2 ~ 12 hours.
Step c)：The compound prepared by step b)（3）Isopropyl methene protection group is removed in acidic aqueous solution, is obtained
Hydroxy styrenes pyridine compounds and their（4）；Wherein, reaction solvent for use is：Water, C1-6Fatty alcohol,N,N- dimethylformamide,
Tetrahydrofuran, C3-8Aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO), preferred solvent is：Water, methyl alcohol, ethanol, 1,
4- dioxane or tetrahydrofuran；Acid used is：Hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C1-6Aliphatic acid, C1-6
Alkyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, preferred acid is：Hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Loprazolam；Acid is in reactant
Mass fraction in system is 0.1%-98%, and preferred mass fraction is 10%-95%, and reaction temperature is 0 ~ 150 DEG C, preferable reaction temperature
It is room temperature ~ 120 DEG C；Reaction time is 30 minutes ~ 24 hours, and preferred reaction time is 1 ~ 8 hour.
Step d)：The compound prepared by step b)（3）Or the compound prepared by step c)（4）In solvent
In with formaldehyde, aminated compounds（HNR1R2）Reacted through Mannich, you can obtain hydroxy styrenes pyridine Mannich bases chemical combination
Thing（I）；Wherein, reaction solvent for use is：C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N, N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, it is excellent
The solvent is selected to be：Methyl alcohol, ethanol, isopropanol,N,N- dimethylformamide, tetrahydrofuran, dichloromethane or toluene；Compound（3）
Or（4）：Formaldehyde：The molar feed ratio of aminated compounds is 1.0：1.0~10.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0：
1.0~5.0：1.0~5.0；Reaction temperature is 0 ~ 120 DEG C, and preferable reaction temperature is room temperature ~ 100 DEG C；Reaction time is 1 ~ 24 small
When, preferred reaction time is 2 ~ 12 hours.
The hydroxy styrenes pyridine Mannich alkaloid compound of gained according to the method described above（I）Contain amino in molecule, should
Amino can be obtained its pharmaceutically acceptable salt with any suitable acid in alkalescence by pharmaceutically conventional salifying method,
Described acid is：Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid（Such as：Formic acid, acetic acid, propionic acid etc.）, oxalic acid,
Benzoic acid, salicylic acid, maleic acid, fumaric acid, butanedioic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid
（Such as：Pyrovinic acid, ethylsulfonic acid etc.）, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more hydroxy styrenes pyridine Manny of therapeutically effective amount
Uncommon alkaloid compound（I）Or its pharmaceutically acceptable salt, the pharmaceutical composition can further containing one or more pharmaceutically
Acceptable carrier or excipient." therapeutically effective amount " refer to cause researcher or the targeted tissue of doctor, system or
The medicine or the amount of medicament of the biological or medical reaction of animal；" composition " refers to by by more than one materials or component
The product for mixing；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or carrier,
Such as：Liquid or solid filler, diluent, excipient, solvent or packing material, they carry or transport certain chemical substance.
Pharmaceutical composition provided by the present invention its preferable ratio is, hydroxy styrenes pyridine Mannich alkaloid compound（I）Or its
Pharmaceutically acceptable salt accounts for gross weight than 2%~99.5% as active component, and remainder is to account for gross weight than less than 98%.
Hydroxy styrenes pyridine Mannich alkaloid compound disclosed in this invention（I）And its pharmaceutically acceptable salt enters
Following bioactivity screening is gone.
（1）Hydroxy styrenes pyridine Mannich alkaloid compound（I）Suppression to acetylcholinesterase and butyrylcholine esterase
System activity
To sequentially adding 1.0 mmol/L acetylthiocholine iodides or iodine bisulfide in 96 orifice plates for BuCh 30 μ L, pH7.4
The μ L of PBS 40, the μ L of testing compound solution 20（DMSO contents are less than 1%）With 10 μ L acetylcholinesterases（Rat
Cortex 5% is homogenized supernatant, and the phosphate buffer of pH7.4 makees homogenate medium）Or butyrylcholine esterase（The supernatant of rat blood serum 25%
Liquid, pH7.4 phosphate buffers make homogenate medium）Solution, after finishing mixing, 37 DEG C of incubation 15min, to addition 0.2% in each hole
5,5 '-two thio-bis- (2- nitrobenzoic acids)（DTNB）The μ L of solution 30 develop the color, and the light for determining each hole at 405nm with ELIASA is close
Degree（OD values）, compare with the blank well for being not added with testing sample, calculate inhibiting rate of the compound to enzyme（Enzyme inhibition rate (%)=(1- samples
Product group OD values/blank group OD values) × 100%）；Five to six concentration of compound are selected, its enzyme inhibition rate is determined, and with the change
The negative logarithm of compound molar concentration and the inhibiting rate linear regression of enzyme, try to achieve molar concentration as chemical combination during 50% inhibiting rate
The IC of thing50.Measurement result shows, the hydroxy styrenes pyridine Mannich alkaloid compound disclosed in the embodiment of the present invention（I）
The effect of significantly inhibiting is respectively provided with to acetylcholinesterase, its IC50It is 0.2 μM ~ 15.0 μM；And hydroxy styrenes pyridine Manny
Uncommon alkaloid compound（I）The inhibitory activity to butyrylcholine esterase is significantly higher than to the inhibitory activity of acetylcholinesterase（Selection
Property be more than 10 times）, illustrate that compound disclosed in this invention has selective inhibitory to acetylcholinesterase.Measurement result
It is also shown that hydroxy styrenes pyridine Mannich alkaloid compound（I）Parent nucleus --- compound（3）Or（4）To acetylcholine ester
Enzyme almost without inhibitory action, its IC50It is all higher than 200 μM.
（2）Hydroxy styrenes pyridine Mannich alkaloid compound（I）To MAOA and the inhibitory activity of B
Recombined human MAO-A is made into 12.5 μ g/mL sample liquids with the kaliumphosphate buffers of pH 7.4 of 100 mM, MAO-B is made into
75 μ g/mL sample liquids.To the μ L of testing compound solution 20, the μ L of monoamine oxidase 80 is added in the orifice plate of black 96, mix, 37 °
C is incubated 15 min at lucifuge, adds 200 μM of Amplex Red reagents, 2U/mL horseradish peroxidases, and 2 mM are to hydroxyl
Phenyl ethylamine（Suppress MAO-A）Or 2 mM benzene methanamines（Suppress MAO-B）Initiation reaction, 37 °C of 20 min of incubation, in multifunctional enzyme mark
On instrument, to fix the nm of excitation wavelength 545, survey 590 nm places fluorescent emission intensity, with kaliumphosphate buffer instead of MAO-A or
MAO-B is blank；Compound suppress monoamine oxidase inhibiting rate computing formula be：100-(IFi)/(IFc) * 100, in formula,
IFiAnd IFcRespectively there is the difference of the fluorescence intensity and blank fluorescence intensity under inhibitor and no inhibitor.Each compound is every
3 multiple holes of secondary measure, every group of experiment is independent in triplicate.Five to six concentration of compound are selected, its enzyme inhibition rate is determined, and
With the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when trying to achieve 50% inhibiting rate is
The IC of the compound50.Measurement result shows, the hydroxy styrenes pyridine Mannich bases chemical combination disclosed in the embodiment of the present invention
Thing（I）The effect of significantly inhibiting is respectively provided with to MAO-B, its IC50It is 0.5 μM ~ 25.0 μM；And to the IC of MAO-A suppression50It is high
In 50.0 μM, illustrate that compound disclosed in this invention has selective inhibitory to MAO-B.
（3）Hydroxy styrenes pyridine Mannich alkaloid compound（I）The measure acted on complexing of metal ion
CuCl is dissolved with methyl alcohol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And testing compound, it is made into the molten of 75 μm of ol/L
Liquid, to 100 μ L testing compound solutions and 100 μ L metal ion solutions are added in 96 orifice plates, mixes, and is stored at room temperature 30 min,
Ultraviolet absorption curve of the mixture in the range of 200-600 nm is recorded on multi-function microplate reader, and with 100 μ L test compounds
Thing solution and 100 μ L methyl alcohol mixed liquors are control, and observation metal ion is red with the maximum absorption band of testing compound mixed liquor
Move the intensity of phenomenon and maximum absorption band.Measurement result shows that the hydroxy styrenes pyridine disclosed in the embodiment of the present invention is graceful
Buddhist nun wishes alkaloid compound（I）Show to Cu2+And Fe2+With selective complexation effect, and to Zn2+And Al3+Almost without complexing
Effect.
（4）Hydroxy styrenes pyridine Mannich alkaloid compound（I）Antioxidation activity（ORAC-FL methods）
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side for being reported
Method is measured, i.e.,：6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids（Trolox）It is made into the PBS of pH7.4
The 10-80 μm of solution of ol/L, fluorescein（fluorescein）The solution of 250 nmol/L is made into the PBS of pH7.4,
2,2 '-azo diisobutyl amidine dihydrochloride（AAPH）Use the preceding solution that 40 mmol/L are made into the PBS of pH7.4.
To 50-10 μm of compound solution and luciferin solution, mixing, 37 °C of incubation 15min of ol/L is added in 96 orifice plates, add
AAPH solution, makes every hole cumulative volume for 200 μ L, mixes, and is immediately placed in multi-function microplate reader, in 485 nm excitation wavelengths and
The min of METHOD FOR CONTINUOUS DETERMINATION 90 under 535 nm launch wavelengths.Area AUC under fluorescence decay curve is calculated, wherein with 1-8 μm of ol/L'sTroloxUsed as standard, to be not added with testing sample as blank, the antioxidation activity results expression of compound isTroloxEquivalent,
Its computing formula is：[(AUC Sample-AUC blank)/(AUCTrolox-AUC blank)]´[(concentration
of Trolox/ concentration of sample)], each compound determines 3 multiple holes every time, and every group of experiment is independently heavy
It is multiple three times.Measurement result shows, the hydroxy styrenes pyridine Mannich alkaloid compound disclosed in the embodiment of the present invention（I）'s
Antioxidation activity isTrolox1.5-4.0 times, illustrate that such compound has strong anti-oxidative activity.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited to
Following embodiments.One of skill in the art, can be right it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
Embodiment 1
Ar is represented（B）During construction unit, hydroxy styrenes pyridine Mannich alkaloid compound（I）The logical method of preparation
4.0 mmol 5- (chloromethyl) -2,2,8- trimethyls -4 are added in reaction bulbH- [1,3] dioxane [4,5-c] pyrrole
Pyridine（1）With 25.0 mmol triethyl phosphites, temperature rising reflux stirring reaction 4.0 hours（Reaction process is tracked with TLC）；Reaction
After end, excessive triethyl phosphite, residue by silicagel column chromatographic purifying are removed under reduced pressure（Eluent：Petroleum ether-acetic acid second
Ester=1:1 v/v）, obtain 2,2,8- trimethyls -4H- [1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylesters（2）, receive
Rate 93.2%；
By 2,2,8- trimethyls -4 obtained in upper stepH- [1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylesters（2）
Full dose is dissolved in 20 ml tetrahydrofurans, is cooled to 0~5 DEG C, adds 8.0 mmol sodium hydrides, and insulated and stirred reacts 30 minutes, so
After add hydroxy benzaldehyde compound（HO-PhCHO）4.0 mmol, continue at 0~5 DEG C of insulated and stirred and react 6-8 hours；Instead
After should terminating, 10% aqueous hydrochloric acid solution terminating reaction is added, then with 10% soda solution neutralization reaction liquid to neutrality, decompression is steamed
Except tetrahydrofuran, residual solution are extracted with 50 ml ethyl acetate, organic layer is filtered after anhydrous sodium sulfate drying, is removed under reduced pressure molten
Agent, residue is purified through column chromatography（Eluent：Petroleum ether-ethyl acetate=2:1 v/v）, obtain corresponding isopropyl methene hydroxy benzenes
Vinylpyridine class compound（3）, yield 65.0%-80.0%；
Take the isopropyl methene hydroxy styrenes pyridine compounds and their that above-mentioned steps are obtained（3）1.0 mmol are dissolved in 6 ml ethanol,
Add the mmol of paraformaldehyde 3.0 and corresponding aminated compounds（HNR1R2）3.0 mmol, 3-10 is small for temperature rising reflux stirring reaction
When（Reaction process is tracked with TLC）, after reaction terminates, remove solvent under reduced pressure, 25 ml ethyl acetate are added in residue, with 10
Ml saturated common salt water washings, organic layer is filtered after anhydrous sodium sulfate drying, removes solvent under reduced pressure, and residue is purified through column chromatography
（Eluent：Petroleum ether-ethyl acetate=1:3 v/v）, obtain corresponding hydroxy styrenes pyridine Mannich alkaloid compound（I）, receive
Rate 25.0%-75.5%, its chemical constitution is passed through1H-NMR、13C-NMR and ESI-MS is confirmed, and the purity of gained object is through HPLC
Measure is all higher than 97.0%.The object structure prepared using above-mentioned logical method is as follows：
Embodiment 2
Ar is represented（A）During construction unit, hydroxy styrenes pyridine Mannich alkaloid compound（I）The logical method of preparation
4.0 mmol 5- (bromomethyl) -2,2,8- trimethyls -4 are added in reaction bulbH- [1,3] dioxane [4,5-c] pyrrole
Pyridine（1）, 10.0 mmol Trimethyl phosphites and 25 ml chlorobenzenes, temperature rising reflux stirring reaction 5.0 hours（Reaction process TLC
Tracking）；After reaction terminates, excessive Trimethyl phosphite and chlorobenzene, residue by silicagel column chromatographic purifying are removed under reduced pressure（Wash-out
Liquid：Petroleum ether-ethyl acetate=1:1 v/v）, obtain 2,2,8- trimethyls -4H- [1,3] dioxane [4,5-c] pyridine -5- methyl
Dimethyl phosphate（2）, yield 90.9%；
By 2,2,8- trimethyls -4 obtained in upper stepH- [1,3] dioxane [4,5-c] pyridine -5- methyl-phosphoric acid dimethyl esters（2）
Full dose is dissolved in 20 ml toluene, is cooled to 0~5 DEG C, adds 10.0 mmol sodium methoxides, reaction 30 minutes is stirred at room temperature, then
Add hydroxy benzaldehyde compound（HO-PhCHO）4.0 mmol, are warming up to 50 DEG C stirring reaction 5-12 hours；Reaction terminates
Afterwards, 10% aqueous hydrochloric acid solution terminating reaction is added, then first is removed under reduced pressure to neutrality with 10% soda solution neutralization reaction liquid
Benzene, residual solution is extracted with 50 ml ethyl acetate, and organic layer is filtered after anhydrous sodium sulfate drying, removes solvent, residue under reduced pressure
Purified through column chromatography（Eluent：Petroleum ether-ethyl acetate=2:1 v/v）, obtain corresponding isopropyl methene hydroxy styrenes pyridines
Compound（3）, yield 57.0%-68.0%；
By isopropyl methene hydroxy styrenes pyridine compounds and their obtained in upper step（3）Full dose add the ml of 15% aqueous hydrochloric acid solution 10 and
In the mixed solution of the ml of ethanol 20, reaction is stirred at room temperature 3.0~7.0 hours（Reaction process is tracked with TLC）, after reaction terminates,
Remove solvent under reduced pressure, 50 ml ethyl acetate are added in residue, organic layer is successively with the sodium bicarbonate aqueous solutions of 25 ml 5% and 20
Ml deionized waters are washed, and are filtered after anhydrous sodium sulfate drying, remove solvent under reduced pressure, and residue is purified through column chromatography（Eluent：
Petroleum ether-ethyl acetate=2:1 v/v）, obtain corresponding hydroxy styrenes pyridine compounds and their（4）, yield 88%-90%；
Take the hydroxy styrenes pyridine compounds and their that above-mentioned steps are obtained（4）1.0 mmol are dissolved in 6 ml ethanol, add poly
The mmol of formaldehyde 3.0 and corresponding aminated compounds（HNR1R2）3.0 mmol, temperature rising reflux stirring reaction 3-10 hours（React into
Journey is tracked with TLC）, after reaction terminates, remove solvent under reduced pressure, 25 ml ethyl acetate are added in residue, eaten with 10 ml saturations
Salt water washing, organic layer is filtered after anhydrous sodium sulfate drying, removes solvent under reduced pressure, and residue is purified through column chromatography（Eluent：
Petroleum ether-ethyl acetate=1:3 v/v）, obtain corresponding hydroxy styrenes pyridine Mannich alkaloid compound（I）, yield 25.0%-
75.5%, its chemical constitution is passed through1H-NMR、13C-NMR and ESI-MS is confirmed, and the purity of gained object determines big through HPLC
In 97.0%.The object structure prepared using above-mentioned logical method is as follows：
The hydroxy styrenes pyridine Mannich alkaloid compound of embodiment 3（I）With acid logical method is prepared into salt
Added in reaction bulb according to the hydroxy styrenes pyridine Mannich alkaloid compound of the gained of above-described embodiment 1 or 2（I）
The 2.0 mmol and ml of methyl alcohol 50, it is sour accordingly to be stirring evenly and then adding into 6.0 mmol, temperature rising reflux stirring reaction 10 minutes, instead
Room temperature is cooled to after should terminating, solvent is removed under reduced pressure, residue acetone recrystallization filters the solid for separating out, obtains final product hydroxy benzenes
Vinylpyridine Mannich alkaloid compound（I）Salt, its chemical constitution warp1H NMR and ESI-MS are confirmed.
Claims (10)
1. a class hydroxy styrenes pyridine Mannich alkaloid compound or its pharmaceutically acceptable salt, it is characterised in that such change
The chemical structure of general formula of compound is such as（I）It is shown：
In formula：R1And R2C is represented independently of one another1~C12Alkyl, benzyl, substituted benzyl, propargyl；NR1R2Also illustrate that nafoxidine
Base, morpholinyl, piperidyl, piperazinyl, 4- by C1~C12Piperazinyl that alkyl is replaced, 4- by benzyl or substituted benzyl institute
Substituted piperazinyl ,-CH2NR1R2Can be in any possible position of phenyl ring with OH；Ar is expressed as follows shown（A）With（B）In appoint
One construction unit；
Above-mentioned term " substituted benzyl " refers to the benzyl replaced by the group that 1-4 is selected from the group on phenyl ring：F、Cl、Br、
I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substitution bases can be in phenyl ring
Any possible position.
2. hydroxy styrenes pyridine Mannich alkaloid compound as claimed in claim 1 or its pharmaceutically acceptable salt, its
It is characterised by that described pharmaceutically acceptable salt is such hydroxy styrenes pyridine Mannich alkaloid compound and hydrochloric acid, hydrogen bromine
Acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, butanedioic acid, tartaric acid,
Citric acid, malic acid, lipoic acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
3. the hydroxy styrenes pyridine Mannich alkaloid compound or its is pharmaceutically acceptable as described in claim any one of 1-2
The preparation method of salt, it is characterised in that the compound can be prepared by the following method and obtain：
In formula：R1、R2Definition and chemical structure of general formula with Ar（I）It is identical；-CH2NR1R2Can be in any possible position of phenyl ring with OH
Put；X represents Cl or Br；R3Represent C1-C12Alkyl；
Step a)：5- (halomethyl) -2,2,8- trimethyls -4H- [1,3] dioxane [4,5-c] pyridine compounds and their（1）In nothing
Solvent or have under solvent condition with phosphite ester（P(OR3)3）Reaction, obtains corresponding picolyl phosphoric acid easter class compound（2）；
Step b)：The compound prepared by step a)（2）With hydroxy benzaldehyde compound under solvent and alkalescence condition
（HO-PhCHO）Condensation, obtains isopropyl methene hydroxy styrenes pyridine compounds and their（3）；
Step c)：The compound prepared by step b)（3）Isopropyl methene protection group, hydroxy benzenes are removed in acidic aqueous solution
Vinylpyridine class compound（4）；
Step d)：The compound prepared by step b)（3）Or the compound prepared by step c)（4）In a solvent with
Formaldehyde, aminated compounds（HNR1R2）Reacted through Mannich, you can obtain hydroxy styrenes pyridine Mannich alkaloid compound
（I）；
Using the hydroxy styrenes pyridine Mannich alkaloid compound of above two method gained（I）Contain amino in molecule, should
Amino can be obtained its pharmaceutically acceptable salt with any suitable acid in alkalescence by pharmaceutically conventional salifying method.
4. the preparation of hydroxy styrenes pyridine Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that in step a), reacting solvent for use is：N,N- dimethylformamide, dimethyl sulfoxide (DMSO), chlorobenzene, dichloro
Benzene, benzene,toluene,xylene or diphenyl ether；Compound（1）：The molar feed ratio of phosphite ester is 1.0：1.0~100.0；Reaction
Temperature is 50 ~ 250 DEG C；Reaction time is 30 minutes ~ 24 hours.
5. the preparation of hydroxy styrenes pyridine Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that in step b), reacting solvent for use is：C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- first
Base tetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, second
Nitrile or C5-8Alkane；Reacting alkali used is：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth gold
Category carbonate, alkali metal hydride, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl morpholine,N-
Methyl piperidine, triethylene diamine, TBAH；Compound（2）：Hydroxy benzaldehyde compound：Alkali mole feeds intake
Than being 1.0：0.9~5.0：1.0~10.0；Reaction temperature is -30 ~ 120 DEG C；Reaction time is 1 ~ 24 hour.
6. the preparation of hydroxy styrenes pyridine Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that in step c), reacting solvent for use is：Water, C1-6Fatty alcohol,N,N- dimethylformamide, tetrahydrochysene furan
Mutter, C3-8Aliphatic ketone, acetonitrile, 1,4- dioxane or dimethyl sulfoxide (DMSO)；Acid used is：Hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphorus
Acid, benzoic acid, C1-6Aliphatic acid, C1-6Alkyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid；Mass fraction of the acid in reaction system be
0.1%-98%；Reaction temperature is 0 ~ 150 DEG C；Reaction time is 30 minutes ~ 24 hours.
7. the preparation of hydroxy styrenes pyridine Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that in step d), reacting solvent for use is：C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- first
Base tetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, second
Nitrile or C5-8Alkane；Compound（3）Or（4）：Formaldehyde：The molar feed ratio of aminated compounds is 1.0：1.0~10.0：1.0~
10.0；Reaction temperature is 0 ~ 120 DEG C；Reaction time is 1 ~ 24 hour.
8. a class pharmaceutical composition, it is characterised in that graceful comprising the hydroxy styrenes pyridine as described in claim any one of 1-2
Buddhist nun wishes alkaloid compound or its pharmaceutically acceptable salt, and the pharmaceutical composition further can pharmaceutically connect containing one or more
The carrier or excipient received.
9. pharmaceutical composition as claimed in claim 8, it is characterised in that the hydroxy styrenes pyridine Mannich bases chemical combination
Thing or its pharmaceutically acceptable salt account for gross weight than 5%~99.5% as active component.
10. hydroxy styrenes pyridine Mannich alkaloid compound as described in claim any one of 1-2 or its can pharmaceutically connect
Purposes of the salt received in treatment and/or prevention nervus retrogression relevant disease medicine is prepared, this kind of nervus retrogression correlation disease
Disease is：Vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis,
Progressive lateral sclerosis of spinal cord, neuropathic pain or glaucoma.
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| CN110003033A (en) * | 2018-01-05 | 2019-07-12 | 四川大学 | Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use |
| CN110003034A (en) * | 2018-01-05 | 2019-07-12 | 四川大学 | A kind of hydroxyl Flurbiprofen Mannich alkaloid compound, preparation method and use |
| CN110003033B (en) * | 2018-01-05 | 2021-06-18 | 四川大学 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
| CN110003034B (en) * | 2018-01-05 | 2021-06-18 | 四川大学 | Hydroxyflurbiprofen Mannich base compounds, and preparation method and application thereof |
| CN111087386A (en) * | 2020-01-02 | 2020-05-01 | 牡丹江医学院 | Compound for treating Alzheimer disease and synthetic method thereof |
| CN115073364A (en) * | 2022-06-20 | 2022-09-20 | 上海毕得医药科技股份有限公司 | Preparation method of 6-nitropyridine-3-alcohol |
| CN115073364B (en) * | 2022-06-20 | 2024-04-05 | 上海毕得医药科技股份有限公司 | Preparation method of 6-nitropyridin-3-ol |
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