CN104003983B - Containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof - Google Patents
Containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof Download PDFInfo
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- CN104003983B CN104003983B CN201410234882.8A CN201410234882A CN104003983B CN 104003983 B CN104003983 B CN 104003983B CN 201410234882 A CN201410234882 A CN 201410234882A CN 104003983 B CN104003983 B CN 104003983B
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- -1 phenylseleno Chemical group 0.000 title claims abstract description 119
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 102000010909 Monoamine Oxidase Human genes 0.000 claims abstract description 40
- 108010062431 Monoamine oxidase Proteins 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims description 56
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 21
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 14
- 239000013067 intermediate product Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229960005070 ascorbic acid Drugs 0.000 claims description 9
- 235000010323 ascorbic acid Nutrition 0.000 claims description 9
- 239000011668 ascorbic acid Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 6
- OWPOPWLPWKSLMS-UHFFFAOYSA-N hydrazine;phenol Chemical compound NN.OC1=CC=CC=C1 OWPOPWLPWKSLMS-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 25
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 238000001514 detection method Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000001425 triazolyl group Chemical group 0.000 description 13
- 238000012512 characterization method Methods 0.000 description 12
- 239000000523 sample Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 0 CC(*C=*)C1OC(c(cc2)ccc2OCC2=C*(Cc3ccccc3)*=*2)=**1C(C)=O Chemical compound CC(*C=*)C1OC(c(cc2)ccc2OCC2=C*(Cc3ccccc3)*=*2)=**1C(C)=O 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 102100028661 Amine oxidase [flavin-containing] A Human genes 0.000 description 4
- 101000694718 Homo sapiens Amine oxidase [flavin-containing] A Proteins 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- BTFHLQRNAMSNLC-UHFFFAOYSA-N clorgyline Chemical compound C#CCN(C)CCCOC1=CC=C(Cl)C=C1Cl BTFHLQRNAMSNLC-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- NYMGNSNKLVNMIA-UHFFFAOYSA-N Iproniazid Chemical compound CC(C)NNC(=O)C1=CC=NC=C1 NYMGNSNKLVNMIA-UHFFFAOYSA-N 0.000 description 2
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 2
- 229940070023 iproniazide Drugs 0.000 description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 2
- 150000002545 isoxazoles Chemical class 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229960003057 nialamide Drugs 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- AELCINSCMGFISI-DTWKUNHWSA-N (1R,2S)-tranylcypromine Chemical compound N[C@@H]1C[C@H]1C1=CC=CC=C1 AELCINSCMGFISI-DTWKUNHWSA-N 0.000 description 1
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- HZVGOEUGZJFTNN-UHFFFAOYSA-N 1-azido-4-chlorobenzene Chemical compound ClC1=CC=C(N=[N+]=[N-])C=C1 HZVGOEUGZJFTNN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OQTNLOZGQASGHN-UHFFFAOYSA-N CCNC1[IH]C1 Chemical compound CCNC1[IH]C1 OQTNLOZGQASGHN-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003705 background correction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229950002858 clorgiline Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 229940087524 nardil Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- OYODOQNYJLSLJE-UHFFFAOYSA-N pyrazol-4-one Chemical class O=C1C=NN=C1 OYODOQNYJLSLJE-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000001420 substituted heterocyclic compounds Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 108010050939 thrombocytin Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a kind of containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof, shown in described structure such as formula (VI 1) containing the substituted bis-heterocyclic compounds of phenylseleno or formula (VI 2), its synthetic route is as follows.The described substituted bis-heterocyclic compounds containing phenylseleno has good monoamine oxidase inhibitory activity, can be used for preparing MAOI.
Description
1, technical field
The present invention relates to a kind of containing the substituted bis-heterocyclic compounds of phenylseleno and preparation and application thereof, especially its application in preparation MAOI.
2, background technology
The complete entitled monoamine oxidoreducing enzyme of monoamine oxidase (monoamine oxidase, MAO, EC1.4.3.4), was found by Balschko in the 1830's, was a kind of enzyme playing an important role neurotransmitter metabolism.It is catalyzed the amine that some organisms produce in brain and peripheral nerve tissue, and oxidative deamination produces hydrogen peroxide.Nineteen sixty-eight, Johnston is divided into two subclass of A and B according to monoamine oxidase to the susceptibility of its irreversible inhibitor clorgyline (clorgiline), and MAOA is sensitive to clorgyline, and MAO-B is insensitive.Further study showed that MAOA has high-affinity to substrate thrombocytin (5-HT), norepinephrine (NE), dopamine (DA) and inhibitor clorgyline;MAO-B then has high-affinity (Kuwahara T, etc., Agric.Biol.Chem., 1990,54,253-257.) to phenethyl amine (PEA), benzene methanamine and inhibitor deprenyl (selegiline).
Research shows that monoamine oxidase, during metabolism dopamine, supervenes the endogenous material such as free radical and hydrogen peroxide, and the exception of its expression and Parkinson's, depression and aggression have extremely close relationship.Along with the gradually quickening of people's rhythm of life, stress is continuously increased, and the incidence of disease of depression rises the most rapidly, it is contemplated that to the year two thousand twenty, will become the second largest disease being only second to coronary heart disease in the world.The initiation of this disease may be relevant with the exception of monoamine oxidase (MAO), and the medicine of MAOI (MAOI) to be a class specifically suppress internal MAO activity, once the fifties first being used to treat depression.Its mechanism is that in minimizing central nervous system, the degraded of monoamine neurotransmitter, increases the concentration of maincenter monoamine transmitters relatively, improves mood, produces antidepressant effect by suppression MAO.Clinical used monoamine oxidase inhibitor has the nardil (Phenelzine) of hydrazine, isoniazid (Isonicotinyl hydrazide), iproniazid (Iproniazid), Nialamide (Nialamide,) etc., non-hydrazine with parnitene (Tranylcypromine) as representative (Kalgutkar, A.S.Chem.Res.Toxicol., 2001,14 (9), 1139-1162.).Owing to these medicine major part toxic and side effects are relatively big and single to the action effect of monoamine oxidase, so seeking low toxicity, respond well MAOI becomes the fresh target of current research.
Nitrogen-containing heterocycle compound all shows the goodst monoamine oxidase inhibitory activity, particularly Mazouz, F. the 1 of report different substituents is waited, 3,4-diazolones compounds derivatives have monoamine oxidase inhibitory activity (Mazouz, F. etc., J Med Chem., 1993,36,6394-63981157-1167).Isoxazole compounds is present in numerous natural products skeletons, is that a class has good biologically active or the material of potential source biomolecule activity, the most gradually becomes important medicine intermediate and lead compound.Such as, isoxazole compounds have the most antibacterial, anti-inflammatory, the BA such as antitumor (He Hongwu etc. agricultural chemicals., 2000,39 (8), 4-7).Isoxazole compound is also in the news and has monoamine oxidase inhibitory activity, and such as, the compound Isocarboxazid having isoxazole and hydrazides both active groups concurrently is first generation MAOI;Liu Bingni report containing the compound of isoxazole ring show certain monoamine oxidase inhibitory activity (Liu Bingni etc., synthesis chemistry., 2011,19 (6), 734-736.).Isoxazole ring or triazole ring are incorporated into diazole ring by the present invention, have synthesized series of new substituted bis-heterocyclic compounds Han phenylseleno, and they have good monoamine oxidase inhibitory activity, are that a good monoamine oxidase of class presses down agent (MAOIs).
3, summary of the invention
First purpose of the present invention be to provide a kind of have good monoamine oxidase inhibitory activity containing the substituted bis-heterocyclic compounds of phenylseleno.
Second object of the present invention is to provide a kind of method described in preparation containing the substituted heterocyclic compound of phenylseleno.
Third object of the present invention is to provide the described application containing the substituted bis-heterocyclic compounds of phenylseleno in preparation MAOI.
Below the technical scheme used for realizing the object of the invention is illustrated.
The invention provides a kind of substituted bis-heterocyclic compounds Han phenylseleno, shown in its structure such as formula (VI):
Wherein, R is selected from the group shown in formula (VIII) or formula (Ⅸ):
In formula (VIII), R1For aryl;
In formula (Ⅸ), R2Selected from one of following groups:
Aryl, benzyl;
Described aryl is unsubstituted or is replaced by one or more in following groups: the alkyl of C1-C3, halogen, the alkoxyl of C1-C3, trifluoromethyl;
R3、R4、R5、R6It is each independently selected from the alkyl of C1-C6.
Concrete, the substituted bis-heterocyclic compounds containing phenylseleno of the present invention can be divided into two categories below:
Further, R1For unsubstituted or by following groups one or more replace phenyl: the alkyl of C1-C3, halogen, the alkoxyl of C1-C3, trifluoromethyl.
Further, R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl.
Further, R3、R4、R5、R6It is each independently selected from the alkyl of C1-C4.
Further, R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl.
Further, described halogen is F, Cl or Br.
The most further, the described substituted bis-heterocyclic compounds containing phenylseleno is one of following:
Present invention also offers a kind of method containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1), described method includes:
(1) preparation of the intermediate product containing phenylseleno shown in formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and the para hydroxybenzene hydrazine shown in formula (VII) is added in reaction vessel; acetic acid is added after being allowed to be completely dissolved; back flow reaction 1-3 hour the most under nitrogen protection, obtains the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;
(2) preparation of the diazoles compound containing phenylseleno shown in formula (IV):
Adding the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride in reaction vessel, the most separated purifying obtains the diazoles compound containing phenylseleno shown in formula (IV);
(3) preparation of the diazoles compound containing terminal triple link shown in formula (V):
The diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), potassium carbonate is added in reaction vessel; it is slowly added to propargyl bromide under stirring; back flow reaction 3~5 hours under nitrogen protection, the most separated purifying obtains the diazoles compound containing terminal triple link shown in formula (V);
(4) preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1):
Make the oxime compound shown in formula (X) and N-chlorosuccinimide (NCS) room temperature reaction 4-5 hour in organic solvent D, be subsequently adding the diazoles compound containing terminal triple link shown in formula (V) and triethylamine to react 5~8 hours, after reaction completely through isolated and purified obtain shown in formula (VI-1) containing the substituted bis-heterocyclic compounds of phenylseleno;
In formula (X), R1The same formula of definition (VI-1).
Further, in step (1), organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile.
Further, in step (1), the molar ratio to hydroxyl hydrazides, acetic acid shown in the positive propionic aldehyde of α-phenylseleno, formula (VII) is 1:1:10~15.
Further, in step (2), the addition volume of acetic anhydride is calculated as (4~6) mL/mmol with the molal quantity of the intermediate product containing phenylseleno shown in formula (III).
Further, in step (2), the reaction time was at 3~4 hours.
Further, in step (3), organic solvent C is selected from one of following: acetone, DMF.
Further, in step (3), the diazoles compound containing phenylseleno shown in formula (IV) is 1:1~1.3:1.2~1.5 with potassium carbonate, the molar ratio of propargyl bromide.
Further, in step (4), organic solvent D is selected from one of following: dichloromethane, chloroform, oxolane.
Further, in step (4), the oxime compound shown in the diazoles compound containing terminal triple link shown in formula (V), formula (X), N-chlorosuccinimide, the molar ratio of triethylamine are 1:1.5~2:1.5~2:2~3.
Present invention also offers a kind of method containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-2), described method includes:
The preparation of the intermediate product containing phenylseleno shown in (a) formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and the para hydroxybenzene hydrazine shown in formula (VII) is added in reaction vessel; acetic acid is added after being allowed to be completely dissolved; back flow reaction 1-3 hour the most under nitrogen protection, obtains the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;
The preparation of the diazoles compound containing phenylseleno shown in (b) formula (IV):
Adding the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride in reaction vessel, the most separated purifying obtains the diazoles compound containing phenylseleno shown in formula (IV);
The preparation of the diazoles compound containing terminal triple link shown in (c) formula (V):
The diazoles compound containing phenylseleno shown in organic solvent C, formula (IV), potassium carbonate is added in reaction vessel; it is slowly added to propargyl bromide under stirring; back flow reaction 3~5 hours under nitrogen protection, the most separated purifying obtains the diazoles compound containing terminal triple link shown in formula (V);
The preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in (d) formula (VI-2):
The diazoles compound containing terminal triple link shown in formula (V) is made to be dissolved in solvent E, it is sequentially added into cupric sulfate pentahydrate and ascorbic acid, the azido compound shown in formula (XI) is added after stirring and dissolving, reaction 6-8 hour is stirred at room temperature, after reaction completely through isolated and purified obtain shown in formula (VI-2) containing the substituted bis-heterocyclic compounds of phenylseleno;
In formula (XI), R2The same formula of definition (VI-2).
Step (a)-step (c) is above-mentioned steps (1)-step (3), and it is prepared details and does not repeats them here.
In step (d), solvent E is selected from one of following: THF and the mixed solvent of water, dimethyl sulfoxide.
In step (d), the diazoles compound containing terminal triple link shown in formula (V), cupric sulfate pentahydrate, ascorbic acid, the molar ratio of azido compound are 1:0.05~0.1:0.15~0.25:1.3~1.6.
The positive propionic aldehyde of α-phenylseleno shown in raw material formula (II) that the present invention uses can be prepared by following equation according to the method that existing document is reported:
The substituted bis-heterocyclic compounds containing phenylseleno of the present invention has good monoamine oxidase inhibitory activity, especially MAO-B inhibitory activity, therefore can be used for preparing monoamine oxidase (especially MAO-B) inhibitor.
The beneficial effects of the present invention is provide a class new have good monoamine oxidase inhibitory activity containing the substituted bis-heterocyclic compounds of phenylseleno.
4, detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that:
The synthesis of the embodiment 1 diazoles compound derivatives VI-1-1. containing isoxazole
1) by the α of equivalent-phenylseleno propionic aldehyde (0.213g; 1mmol) adding in the round-bottomed flask containing 20ml ethanol with para hydroxybenzene hydrazine (1mmol, 0.152g), stirring is allowed to be completely dissolved; add 800 μ L acetic acid, back flow reaction 3h under nitrogen protection.After TLC detection reaction completely, drain ethanol, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing, anhydrous Na2SO4It is dried, concentrates, obtain intermediate product (III) crude product containing phenylseleno.
2) being joined by the product (III) (1mmol) obtained in the acetic anhydride of 5mL, heating reflux reaction 3h under nitrogen protection, solution colour becomes salmon pink and has suspension to generate.After TLC detection reaction completely, drain acetic anhydride, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing removes the acetic anhydride do not drained, then uses anhydrous Na2SO4It is dried, concentrates, through thin plate chromatography isolated product (IV), productivity 75%.
3) 1mmol (0.390g) compounds Ⅳ is dissolved in 20mL acetone; add (1.5mmol, 0.207g) potassium carbonate, under stirring, be slowly added to (1.2mmol; 0.143g) propargyl bromide, under nitrogen protection back flow reaction 3h.After TLC detection reaction completely, drain acetone, add 20mLCH2Cl2, use saturated Na2CO3Solution (3 × 20mL) solution washing, anhydrous Na2SO4It is dried, concentrates, after thin plate chromatographs, obtain compound V.
4) first the NCS (2mmol, 0.268g) of methylbenzene oxime (2mmol, 0.272g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 4h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) and react 6 hours, after TLC detection major part reaction completely, add saturated sodium-chloride layering, organic phase saturated sodium-chloride washing (30mL × 3), organic phase anhydrous magnesium sulfate is dried, and concentrates, thin plate chromatographs to obtain VI-1-1., productivity 82.5%.Characterization of The Products method:1H NMR by Bruker Avance nmr determination,13C NMR, by Bruker Avance nmr determination, uses CDCl3Making solvent, TMS makees internal standard.FT-IR is used KBr pressed disc method by Bruker Tensor27 type determination of infrared spectroscopy, solid, and liquid uses liquid-film method.Result is as follows:
1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3) δ 7.70 (d, J=7.9Hz, 2H), 7.62 (d, J=7.8Hz, 2H), 7.52-7.48 (m, 4H), 7.37-7.17 (m, 5H), 6.92 (d, J=8.5Hz, 1H), 6.35 (s, 1H), 4.10 (dd, J=49.1,14.1Hz, 1H), 2.46 (s, 2H), 2.40 (s, 3H), 1.62 (s, 3H), 1.25 (d, J=4.6Hz, 3H) .IR νmax(cm-1):3375,2971,1767,1665,1599,1562,1508,1493,1432,1397,1210,1193,1122,1087,927,891,789,690,525,480.MS(ESI)m/z562.1(M+H)+.
The synthesis of the embodiment 2 diazoles compound derivatives VI-1-2. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of methoxybenzene oxime (2mmol, 0.288g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-2., productivity 85% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75-7.72 (m, 4H), 7.68-7.64 (m, 4H), 7.30 (d, J=3.5Hz, 2H), 7.12-7.10 (m, 3H), 6.99 (d, J=8.8Hz, 1H), 6.62 (s, 1H), 5.24 (s, 2H), 3.94-3.62 (m, 1H), 3.85 (s, 3H), 2.31 (s, 3H), 1.34 (d, J=7.2Hz, 3H);IRνmax(cm-1):3120,2976,2920,2820,1665,1607,1580,1562,1504,1455,1409,1234,1210,1167,1122,1098,1026,927,803,708,690,503,414,338.MS(ESI)m/z578.1(M+H)+.
The synthesis of the embodiment 3 diazoles compound derivatives VI-1-3. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of chlorobenzene oxime (2mmol, 0.313g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-3., productivity 71% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.68-7.60 (m, 4H), 7.52 (d, J=8.5Hz, 2H), 7.37 7.17 (m, 7H), 6.92 (d, J=8.5Hz, 1H), 6.35 (s, 1H), 4.10 (dd, J=49.1,14.1Hz, 1H), 2.47 (s, 2H), 2.40 (s, 3H), 1.25 (d, J=4.6Hz, 3H);IRνmax(cm-1):3031,2922,2867,1884,1760,1618,1578,1551,1487,1445,1398,1376,1206,1175,1109,1088,1038,1014,938,802,739,630,483,376.MS(ESI)m/z582.1(M+H)+,584.1(M+2+H)+.
The synthesis of the embodiment 4 diazoles compound derivatives VI-1-4. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of fluorobenzene oxime (2mmol, 0.280g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-4., productivity 78% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75 (d, J=9.0Hz, 2H), 7.68-7.64 (m, 4H), 7.33-7.28 (m, 4H), 7.16 (d, J=1.7Hz, 2H), 7.13-7.10 (m, 1H), 6.92 (d, J=8.7Hz, 1H), 6.63 (s, 1H), 4.10 (dd, J=49.1,14.1Hz, 1H), 2.46 (s, 2H), 2.32 (s, 3H), 1.37-1.35 (m, 3H);IRνmax(cm-1):3042,2927,1708,1613,1601,1551,1507,1454,1409,1223,1158,1114,1026,1019,842,814,730,678,501,452,422..MS(ESI)m/z566.1(M+H)+.
The synthesis of the embodiment 5 diazoles compound derivatives VI-1-5. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first the NCS (2mmol, 0.268g) of trifluoromethylbenzene oxime (2mmol, 0.380g) Yu equivalent will be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-5., productivity 72% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.75-7.56 (m, 4H), 7.28-7.25 (m, 4H), 7.16-7.13 (m, 2H), 7.10-7.03 (m, 3H), 6.69-6.68 (m, 1H), 6.64 (s, 1H), 5.27 (s, 2H), 3.86 (dd, J=14.1,9.8Hz, 1H), 2.31 (s, 3H), (1.34 d, J=7.2Hz, 3H);IRνmax(cm-1):3475,3390,
2971,1767,1665,1626,1551,1524,1444,1324,1210,1184,1157,1110,1063,1010,927,830,691,599,505,428.MS(ESI)m/z616.1(M+H)+.
The synthesis of the embodiment 6 diazoles compound derivatives VI-1-6. containing isoxazole
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) first will pair between the NCS (2mmol, 0.268g) of bromobenzene oxime (2mmol, 0.402g) and equivalent be dissolved in 20mLCH2Cl2At room temperature react 3h, add compound V (1mmol, 0.388g) and be added dropwise to triethylamine (2mmol, 0.28mL) react 6 hours, after TLC detection major part reaction completely, subsequent treatment such as embodiment 1 step 4, VI-1-6., productivity 76% is chromatographed to obtain through thin plate.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.99-7.93 (m, 4H), 7.75 (d, J=7.8Hz, 2H), 7.68 (d, J=4.6Hz, 2H), 7.36-7.32 (m, 2H), 7.26-7.23 (m, 3H), 6.87-6.82 (m, 1H), 6.58 (s, 1H), 5.21 (s, 2H), 3.97-3.92 (m, 1H), 2.34 (s, 3H), 1.36 (d, J=8.6Hz, 3H);IRνmax(cm-1):3058,2917,1708,1629,1601,1568,1587,1473,1411,1214,1162,1115,1073,997,870,834,772,679,664,452,426.MS(ESI)m/z626.0(M+H)+,628.0(M+2+H)+.
Embodiment 7: the preparation of the diazoles compound VI-2-1 containing triazole ring
1) operation is such as embodiment 1 step 1
2) operation is such as embodiment 1 step 2
3) operation is such as embodiment 1 step 3
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 1-azido ethyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 6h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-1. containing triazole ring, productivity 86%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.81-7.58 (m, 2H), 7.61 (t, J=7.7Hz, 1H), 7.50-7.32 (m, 3H), 7.34-7.21 (m, 3H), 7.03 (s, 1H), 6.49-6.48 (m, 1H), 5.42-5.26 (m, 2H), 5.16 (dd, J=20.4,2.4Hz, 1H), 4.31-4.21 (m, 4H), 2.38-2.20 (m, 2H), 1.94 (s, 3H), (1.87 d, J=11.5Hz, 3H), 0.94 (t, J=20.1Hz, 3H);IRνmax(cm-1):3347,3155,2965,1708,1551,1530,1494,1454,1379,1309,1255,1132,1114,1082,970,896,788,764,724,660,452,440.MS(ESI)m/z572.1(M+H)+.
Embodiment 8: the preparation of the diazoles compound VI-2-2 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.10mmol) and ascorbic acid (Vc, 0.25mmol), add 4-triazoacetic acid methyl esters (1.6mmol) after stirring and dissolving, stirring at normal temperature reaction 7h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-2. containing triazole ring, productivity 82.5%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 7.96-7.74 (m, 2H), 7.76-7.60 (m, 2H), 7.65-7.50 (m, 2H), 7.52-7.29 (m, 3H), 7.32-7.18 (m, 1H), 6.59 (d, J=6.8Hz, 1H), 5.22 (s, 2H), 4.82 (dd, J=10.8,5.3Hz, 1H), 2.07 (s, 3H), 1.45-1.43 (m, 2H), 1.76 (d, J=7.0Hz, 3H), 0.97 (s, 3H);IRνmax(cm-1):3639,3147,2922,1738,1511,1466,1436,1394,1364,1319,1252,1234,1123,1058,973,922,890,871,796,769,722,622,450,420.MS(ESI)m/z544.1(M+H)+.
Embodiment 9: the preparation of the diazoles compound VI-2-3 containing triazole ring
Operation is such as embodiment 1 step 1;
1) operation is such as embodiment 1 step 2;
2) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 4-azido methyl propionate (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-3 containing triazole ring, productivity 81.8%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.22 (d, J=1.9Hz, 2H), 7.94 (d, J=8.0Hz, 2H), 7.63-7.58 (m, 2H), 7.58-7.53 (m, 3H), 7.10-7.06 (m, 1H), 6.52-6.50 (m, 1H), 5.25-5.21 (m, 2H), 5.65 (s, 2H), 4.68 (dd, J=12.6,8.4Hz, 1H), 2.28 (s, 3H), 1.76 (s, 2H), 1.34-1.32 (m, 3H), 1.01-0.98 (m, 3H);IRνmax(cm-1):3287,2981,1768,1741,1500,1455,1384,1316,1271,1250,1189,1144,1098,1055,1020,976,879,806,754,722,618,520,480.MS(ESI)m/z558.1(M+H)+.
Embodiment 10: the preparation of the diazoles compound VI-2-4 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add triazobenzene (1.5mmol), stirring at normal temperature reaction 8h after stirring and dissolving, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-4. containing triazole ring, productivity 86.9%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.22-7.93 (m, 4H), 7.70-7.67 (m, 4H), 7.58 (d, J=7.9Hz, 2H), 7.43-7.38 (m, 4H), 7.09 (s, 1H), 5.81-5.80 (m, 1H), 5.43 (s, 2H), 3.98 (dd, J=18.6,9.8Hz, 1H), 2.48 (s, 3H), 1.48 (d, J=6.8Hz, 3H);IRνmax(cm-1):3059,2953,2925,1787,1707,1552,1546,1493,1438,1405,1349,1210,1188,1012,987,865,745,695,626,525,420.MS(ESI)m/z548.1(M+H)+.
Embodiment 11: the preparation of the diazoles compound VI-2-5 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.05mmol) and ascorbic acid (Vc, 0.15mmol), add 4-azido chlorobenzene (1.5mmol) after stirring and dissolving, stirring at normal temperature reaction 8h, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-5. containing triazole ring, productivity 87%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.12 (s, 1H), 7.90 (d, J=8.5Hz, 2H), 7.49-7.35 (m, 5H), 7.24 (m, 3H), 7.07 (d, J=7.7Hz, 2H), 6.98 (s, 1H), 5.71 (d, J=4.1Hz, 1H), 5.42 (s, 2H), (4.38 dd, J=16.2,8.6Hz, 1H), 2.82 (s, 3H), 1.49-1.45 (m, 3H);IRνmax(cm-1):3061,2951,1738,1707,1566,1545,1492,1438,1409,1352,1218,1114,1070,937,862,737,693,674,525,468.MS(ESI)m/z582.1(M+H)+,584.1(M+H)+.
Embodiment 12: the preparation of the diazoles compound VI-2-6 containing triazole ring
1) operation is such as embodiment 1 step 1;
2) operation is such as embodiment 1 step 2;
3) operation is such as embodiment 1 step 3;
4) compound V (1mmol) is dissolved in 10mL THF:H2In O=1:1 (volume ratio), it is sequentially added into CuSO4.5H2O (0.10mmol) and ascorbic acid (Vc, 0.25mmol), add nitrine toluene (1.5mmol), stirring at normal temperature reaction 8h after stirring and dissolving, course of reaction TLC detection is followed the trail of, and reacts concentrated solvent after complete cooling, uses CH2Cl2Extraction (3 × 20mL), merges after organic phase is repeatedly washed and adds anhydrous MgSO4It is dried, 30 DEG C of evaporation and concentration, after thin-layer chromatography is isolated and purified, obtains the diazole compounds VI-2-6 containing triazole ring, productivity 86.1%.Characterization of The Products result is as follows:
1H NMR(400MHz,CDCl3) δ 8.24 (d, J=7.9Hz, 1H), 7.95 (d, J=8.3Hz, 2H), 7.73-7.68 (m, 1H), 7.63 (s, 1H), 7.59 (d, J=8.3Hz, 2H), 7.45-7.42 (m, 2H), 7.32-7.38 (m, 5H), 7.23-7.19 (m, 1H), 5.64-5.62 (m, 1H), 5.42 (s, 2H), 4.99-4.96 (m, 2H), 3.98 (dd, J=21.4,12.6Hz, 1H), 2.81 (s, 3H) .1.28-1.21 (m, 3H);IRνmax(cm-1):3066,2950,2941,1787,1708,1551,1540,1444,1405,1349,1218,1116,1009,927,865,715,695,653,586,480.MS(ESI)m/z562.1(M+H)+.
Embodiment 13: monoamine oxidase inhibitory activity detects
(1) sample preparation
The compound (VI-1)~(VI-12) that embodiment 1~12 are prepared are dissolved in dimethyl sulfoxide (DMSO) (DMSO), be made into 10 respectively, 50,75,100, the sample liquid of 150mmol/L concentration gradient, be designated as sample 1~12.
(2) the substituted bis-heterocyclic compounds Han phenylseleno (VI) is to monoamine oxidase-A inhibitory activity detection method
The sample 1~12 that 10 μ L (concentration 5mg/mL) monoamine oxidase-A (MAO-A) and 4 μ L step (1) prepare is added respectively in 12 parts of EP pipes equipped with 381 μ L borate buffer (pH=8.4), mixing, mixture is reacted in 38 DEG C of water-baths 3h again, state the most again up and 12 parts of EP pipes add probe 7-(3-aminopropan the epoxide)-4-methylcoumarin (20mmol/ml) shown in 2.5 μ L formula (XII) and the bovine serum albumin (BSA of 2.5 μ L, concentration 60mg/mL), and EP pipe is placed in 38 DEG C of water-baths continuation reaction 3h.The enzyme detecting the enzyme of unchecked dose is simultaneously needed to live, in the EP pipe equipped with 385 μ L borate buffer (pH=8.4), i.e. add 10 μ L monoamine oxidase-A (MAO-A), reacting 3h in 38 DEG C of water-baths, the BSA adding 2.5 μ L probe (20mmol/ml) and 2.5 μ L the most also reacts 3h in 38 DEG C of water-baths.
In each EP pipe (microcentrifugal tube), finally take out 100 μ L add in 96 orifice plates and detect sample with global function sepectrophotofluorometer (λ ex/ λ em=365/460nm) (spectraMax M, molecule instrument company of the U.S.).The IC of sample 1~12 is calculated according to the fluorescent value surveyed50, compound (VI-1)~(VI-12) are shown in Table 1 to monoamine oxidase-A activity suppression test result.
The inhibition of compound half-inhibition concentration (IC50) represent.IC50Referring to the concentration of inhibitor when " reaction " is suppressed half, compound rejection ability is the strongest, and this numerical value is the lowest.
IC50Can calculate using the following method:
1) detect and calculate the most enzyme-added and probe buffer solution average fluorescent strength (FM);
2) average fluorescent strength (wanting background correction value) of each component enzymes containing variable concentrations gradient inhibitor is calculated;
3) do the linear regression of relation between the concentration (C) of inhibitor and fluorescence intensity (F) according to the fluorescence intensity of each component enzymes of variable concentrations gradient inhibitor, set up and obtain equation: F=aC+b (determine equation coefficient a by regression straight line and cut the b that crouches);
4) according to equation, F=1/2F is soughtMUnder corresponding inhibitor concentration, can obtain inhibiting rate is inhibitor concentration when 50%, is IC50。
(3) monoamine oxidase-B inhibitory activity is tested by the substituted bis-heterocyclic compounds Han phenylseleno (VI)
Changing MAO-A into MAO-B, other operate same step (2), the results are shown in Table 1.
The substituted bis-heterocyclic compounds containing phenylseleno (VI) of table 1 embodiment 1~12 preparation is to MAOA and the inhibitory activity of B
A: inhibitory activity IC50Representing, each sample does 3 parallel group, takes 5 concentration gradients;
B: the selectivity SI of enzyme is represented, SI:selectivity index=IC50(MAO-A)/IC50(MAO-B)
c:ND:too large that were not detected(>1.0mM).
As can be seen from Table 1, compound (VI-1-1)~(VI-1-5) and (VI-2-1)~(VI-2-6) have inhibitory activity to MAOA, and wherein compound (VI-1-1)~(VI-1-5) have stronger inhibitory activity;Compound (VI-1-1)~(VI-1-6) and (VI-2-1)~(VI-2-6) have inhibitory activity to MAO-B, wherein compound (VI-1-1)~(VI-1-6) and (VI-2-2)~(VI-2-6) have stronger inhibitory activity, particularly compound (VI-1-1)~(VI-1-5) to have extremely strong inhibitory activity.
Claims (8)
1. a substituted bis-heterocyclic compounds Han phenylseleno, shown in its structure such as formula (VI):
Wherein, R is selected from the group shown in formula (VII) or formula (VIII):
In formula (VII), R1For phenyl that is unsubstituted or that replaced by one or more in following groups: C1-C3
Alkyl, halogen, the alkoxyl of C1-C3, trifluoromethyl;
In formula (VIII), R2Selected from one of following groups:
Phenyl, the phenyl of halogen substiuted, benzyl;
R3、R4、R5、R6It is each independently selected from the alkyl of C1-C6.
2. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: R3、
R4、R5、R6It is each independently selected from the alkyl of C1-C4.
3. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: described
Halogen be F, Cl or Br.
4. the substituted bis-heterocyclic compounds Han phenylseleno as claimed in claim 1, it is characterised in that: described
The substituted bis-heterocyclic compounds containing phenylseleno be one of following:
5. prepare the method as claimed in claim 1 containing the substituted bis-heterocyclic compounds of phenylseleno, described
Shown in structure such as formula (VI-1) containing the substituted bis-heterocyclic compounds of phenylseleno, in formula (VI-1), R1Definition
Same formula (VI), described method includes:
(1) preparation of the intermediate product containing phenylseleno shown in formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII) is added in reaction vessel
Shown para hydroxybenzene hydrazine, adds acetic acid, the most under nitrogen protection back flow reaction 1-3 after being allowed to be completely dissolved
Hour, obtain the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;Described
Organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile;
(2) preparation of the diazoles compound containing phenylseleno shown in formula (IV):
In reaction vessel, add the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride, reacted
Through the isolated and purified diazoles compound containing phenylseleno obtained shown in formula (IV) after Biing;
(3) preparation of the diazoles compound containing terminal triple link shown in formula (V):
Reaction vessel adds the diazoles compound containing phenylseleno shown in organic solvent C, formula (IV),
Potassium carbonate, is slowly added to propargyl bromide under stirring, under nitrogen protection back flow reaction 3~5 hours, has reacted
Through the isolated and purified diazoles compound containing terminal triple link obtained shown in formula (V) after Biing;Described organic molten
Agent C is selected from one of following: acetone, N,N-dimethylformamide;
(4) preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in formula (VI-1):
Make the oxime compound shown in formula (X) and N-chlorosuccinimide room temperature in organic solvent D anti-
Answer 4-5 hour, be subsequently adding the diazoles compound containing terminal triple link shown in formula (V) and triethylamine is anti-
Answer 5~8 hours, after reaction completely through isolated and purified obtain shown in formula (VI-1) substituted double containing phenylseleno
Heterocyclic compound;Described organic solvent D is selected from one of following: dichloromethane, chloroform, oxolane;
In formula (X), R1The same formula of definition (VI-1).
6. prepare the method as claimed in claim 1 containing the substituted bis-heterocyclic compounds of phenylseleno, described
Shown in structure such as formula (VI-2) containing the substituted bis-heterocyclic compounds of phenylseleno, in formula (VI-2), R2Definition
Same formula (VI), described method includes:
The preparation of the intermediate product containing phenylseleno shown in (a) formula (III):
The positive propionic aldehyde of α-phenylseleno shown in organic solvent B, formula (II) and formula (VII) is added in reaction vessel
Shown para hydroxybenzene hydrazine, adds acetic acid, the most under nitrogen protection back flow reaction 1-3 after being allowed to be completely dissolved
Hour, obtain the intermediate product containing phenylseleno shown in formula (III) through isolated and purified after reaction completely;Described
Organic solvent B is selected from one of following: ethanol, oxolane, acetonitrile;
The preparation of the diazoles compound containing phenylseleno shown in (b) formula (IV):
In reaction vessel, add the intermediate product containing phenylseleno shown in formula (III) and acetic anhydride, reacted
Through the isolated and purified diazoles compound containing phenylseleno obtained shown in formula (IV) after Biing;
The preparation of the diazoles compound containing terminal triple link shown in (c) formula (V):
Reaction vessel adds the diazoles compound containing phenylseleno shown in organic solvent C, formula (IV),
Potassium carbonate, is slowly added to propargyl bromide under stirring, under nitrogen protection back flow reaction 3~5 hours, has reacted
Through the isolated and purified diazoles compound containing terminal triple link obtained shown in formula (V) after Biing;Described organic molten
Agent C is selected from one of following: acetone, N,N-dimethylformamide;
The preparation containing the substituted bis-heterocyclic compounds of phenylseleno shown in (d) formula (VI-2):
Make the diazoles compound containing terminal triple link shown in formula (V) be dissolved in solvent E, be sequentially added into five
Brochanite and ascorbic acid, add the azido compound shown in formula (XI), be stirred at room temperature after stirring and dissolving
React 6-8 hour, after reaction completely through isolated and purified obtain shown in formula (VI-2) substituted double containing phenylseleno
Heterocyclic compound;Described solvent E is selected from one of following: THF and the mixed solvent of water, dimethyl sulfoxide;
In formula (XI), R2The same formula of definition (VI-2).
7. as claimed in claim 1 press down preparing monoamine oxidase containing the substituted bis-heterocyclic compounds of phenylseleno
Application in preparation.
Apply the most as claimed in claim 7, it is characterised in that: described MAOI is
MAO-B inhibitor.
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CN102250048A (en) * | 2011-06-03 | 2011-11-23 | 浙江工业大学 | 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof |
WO2012030165A2 (en) * | 2010-08-31 | 2012-03-08 | 서울대학교산학협력단 | Use of the fetal reprogramming of a ppar δ agonist |
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CN102250048A (en) * | 2011-06-03 | 2011-11-23 | 浙江工业大学 | 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof |
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