CN102911117A - Naphthylamine derivative and purpose thereof - Google Patents
Naphthylamine derivative and purpose thereof Download PDFInfo
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- CN102911117A CN102911117A CN2012104306337A CN201210430633A CN102911117A CN 102911117 A CN102911117 A CN 102911117A CN 2012104306337 A CN2012104306337 A CN 2012104306337A CN 201210430633 A CN201210430633 A CN 201210430633A CN 102911117 A CN102911117 A CN 102911117A
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- ethyl
- amino
- benzo
- isoquinoline
- diketone
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- 0 Cc1c(C)c(*)c(*)c(*)c1* Chemical compound Cc1c(C)c(*)c(*)c(*)c1* 0.000 description 4
- SEWZPYPLFLUCCE-UHFFFAOYSA-N NCCN(C(c1c2c3cccc2ccc1)=O)C3=O Chemical compound NCCN(C(c1c2c3cccc2ccc1)=O)C3=O SEWZPYPLFLUCCE-UHFFFAOYSA-N 0.000 description 2
- URIVYBLQEIFBAU-UHFFFAOYSA-N BrCCOc1ccc2OCOc2c1 Chemical compound BrCCOc1ccc2OCOc2c1 URIVYBLQEIFBAU-UHFFFAOYSA-N 0.000 description 1
- LFBNFLYWKYDHHL-UHFFFAOYSA-N CC(C)(C)OC(NCCN(C(c(c1c2cc3)cccc1c3OC)=O)C2=O)=O Chemical compound CC(C)(C)OC(NCCN(C(c(c1c2cc3)cccc1c3OC)=O)C2=O)=O LFBNFLYWKYDHHL-UHFFFAOYSA-N 0.000 description 1
- KMMGKZUGBCYIMI-UHFFFAOYSA-N CC(C)(C)OC(NCCN(C(c(c1c2cc3)cccc1c3[N+]([O-])=O)=O)C2=O)=O Chemical compound CC(C)(C)OC(NCCN(C(c(c1c2cc3)cccc1c3[N+]([O-])=O)=O)C2=O)=O KMMGKZUGBCYIMI-UHFFFAOYSA-N 0.000 description 1
- WTJWXOVKBCITCR-UHFFFAOYSA-N COc(c1c2c(C(N3CCN)=O)ccc1)ccc2C3=O Chemical compound COc(c1c2c(C(N3CCN)=O)ccc1)ccc2C3=O WTJWXOVKBCITCR-UHFFFAOYSA-N 0.000 description 1
- CQUFIZYYNZYAQA-UHFFFAOYSA-N COc(cc1)ccc1SCCBr Chemical compound COc(cc1)ccc1SCCBr CQUFIZYYNZYAQA-UHFFFAOYSA-N 0.000 description 1
- DUYWDESTXRBKCT-UHFFFAOYSA-N COc(cc1)ccc1SCCNCCN(C(c1c2c3cccc2ccc1)=O)C3=O Chemical compound COc(cc1)ccc1SCCNCCN(C(c1c2c3cccc2ccc1)=O)C3=O DUYWDESTXRBKCT-UHFFFAOYSA-N 0.000 description 1
- JQLGDRPHZXZLKU-UHFFFAOYSA-N O=C(c1c2cccc1)N(CCNCCN(C(c1c3c4cccc3ccc1)=O)C4=O)C2=O Chemical compound O=C(c1c2cccc1)N(CCNCCN(C(c1c3c4cccc3ccc1)=O)C4=O)C2=O JQLGDRPHZXZLKU-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N O=C(c1c2cccc1)NC2=O Chemical compound O=C(c1c2cccc1)NC2=O XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- ZTAWLVLQHQPJCS-UHFFFAOYSA-N O=C(c1cccc2cccc3c12)N(CCNCCOc1ccc2OCOc2c1)C3=O Chemical compound O=C(c1cccc2cccc3c12)N(CCNCCOc1ccc2OCOc2c1)C3=O ZTAWLVLQHQPJCS-UHFFFAOYSA-N 0.000 description 1
- CHZXTOCAICMPQR-UHFFFAOYSA-N O=C(c1ccccc11)N(CCBr)C1=O Chemical compound O=C(c1ccccc11)N(CCBr)C1=O CHZXTOCAICMPQR-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The inventor of the invention utilizes the medicinal chemical principle to design and synthetize a series of novel naphthylamine derivatives, and performs an inhibitory activity test of the kind of derivative on human N-acetyl amino glycosidase. The test result shows that the inhibitory activity effect is good, and the inhibition effect of some compounds is obviously higher than that of reference compounds reported in literatures. According to the invention, the naphthylamine derivative is free of a glycosyl structure; and the synthesis method is relatively simpler. Therefore, the naphthylamine derivative lays foundation for the development of new medicines used for curing illness relative to human Beta-N-acetyl amino glycosidase.
Description
Technical field
The present invention relates to a kind of naphthalimide derivative and uses thereof (as the application of human beta-N-acetylhexosaminidase inhibitor).
Background technology
Carbohydrate is brought into play critical function in vivo, not only occupies core status in energy metabolism, and participate in comprising keep that organism structure is complete, multiple physiology and the pathologic processes such as diffusion of cell recognition, signal conduction, inflammatory reaction and cancer cells.Because the physiological process that carbohydrate participates in is so complicated, therefore, the enzyme that participates in the carbohydrate metabolic process also is of a great variety.The enzyme of the participation carbohydrate hydrolysis that up to the present, has been found that just adheres to 114 families separately.
Beta-N-acetylhexosaminidase (β-N-acetyl-D-hexosaminidase, EC3.2.1.52) in the mankind and the Mammals lysosome participates in the hydrolysis of glycosylation part in the multiple saccharide complex.Human body contains 3 kinds of beta-N-acetylhexosaminidases, all is the dimers that are made of α-subunit and β-subunit.Wherein, beta-N-acetylhexosaminidase A is by a α-subunit and the different poly-binary that β-subunit consists of.Beta-N-acetylhexosaminidase is to be responsible for the enzyme that hydrolysis is positioned at the N-acetylhexosamine of various saccharide complex non-reducing ends.Because this enzyme is widely distributed and participate in the interior many important physiology of organism and pathologic process, is therefore paid close attention to by the different field investigators, wishes to realize the physiology of this enzyme participation or the regulation and control of pathologic process by the adjusting to this enzyme activity always.There is certain difference in beta-N-acetylhexosaminidase aspect physiological distribution, structure and the catalytic mechanism, therefore, might utilize the inhibitor of these difference design alternatives fully, to reach the purpose of particular physiological function in the regulation and control organism.
This enzyme is at the auxiliary lower hydrolysis physiology substrate Ganglioside GM2 of GM2 activator, and this physiological process is most important for human health.The sudden change of associated protein can cause the accumulation of Sphingolipids,sialo in the neurone lysosome, causes serious gangliosidosis, such as Tay-Sachs disease and Sandhoff disease etc.
Although this class disease sickness rate is low, but the destructiveness to human body is very large, the research of drug molecule companion in this class disease is more. and the drug molecule companion of sudden change lysosomal enzyme is generally the competitive inhibitor of this fermentoid, can be incorporated into the active centre with mutant enzyme, assist it correctly folding in endoplasmic reticulum, thereby avoid degradation pathway, correctly be transported to lysosome, there is the metabolism substrate of high density in lysosome, be at war with the drug molecule that is incorporated into mutant enzyme, so that zymoprotein and drug molecule dissociate, act on the eubolism substrate.
Adopt the drug molecule companion to treat lysosomal storage disease, its application prospect is very wide. and drug molecule companion therapy is by oral lysosomal enzyme inhibitor, directly recover the function of endogenous lysosomal enzyme, and drug molecule can pass through hemato encephalic barrier treatment central nervous system relevant store up disease, easier than existing other treatment method (as: enzyme replacement treatment and substrate reduce therapy), be more suitable for long-term treatment.Enzyme strengthens therapy and is attempted being used for the treatment of multiple inherited disease.Because the enzyme activity that many lysosomes store up disease often only to be needed to recover 5-10% just can be cured, and therefore is considered to more potential.
So far, the human amino hexoside enzyme inhibitors of reporting all is based on the structure of glycosyl, may run into a lot of problems in structure of modification and actual application, therefore has the investigator exploring aspect the non-glycosyl inhibition agent of screening.The people such as Tropak utilize the method for high flux screening to obtain that several wherein a kind of inhibition of bisnaphthalimides is best not based on the brand-new inhibitor structure of glycosyl, but because its clinical toxicity is larger, can not be used for the treatment of research.
Given this, exploitation and the initiative based on the novel human hexosaminidase inhibitor of non-glycosyl just seems very necessary.
Summary of the invention
The present inventor uses the pharmaceutical chemistry principle, has designed and synthesized the naphthalimide derivative of series of novel, and done the inhibition active testing of this analog derivative to human N-acetyl hexosaminidase, test result shows: it is active that the naphthalimide analog derivative of the present invention's design and invention demonstrates good inhibition to human N-acetyl hexosaminidase, and the part of compounds inhibition is apparently higher than the control compound of bibliographical information.Because the not sugary based structures of naphthalimide derivative that the present invention designs and synthesizes, its synthetic method is relatively simple, and thus, the new drug initiative that is used for the treatment of the disease relevant with human beta-N-acetylhexosaminidase for exploitation is laid a good foundation.
One object of the present invention is, a kind of naphthalimide derivative of novelty is provided, and described naphthalimide derivative is compound shown in the formula I, or it is at pharmacologically acceptable salts:
Among the formula I, R
1Be hydrogen (H), C
1～C
4Alkoxyl group, C
1～C
4The amino that alkyl replaces (
R
3And R
4Independently be selected from respectively C
1～C
4A kind of in the alkyl), or halogen (F, Cl, Br or I);
R
2Be hydrogen (H), hydroxyl (OH) or amino (NH
2) C that replaces
1～C
4Alkyl, or group shown in the formula II:
Among the formula II, X is O, S, and NH, or
M is 0～6 integer; N is 0 or 1;
A is phenyl, substituted-phenyl, and the nitrogenous quinary heterocyclic radical of nitrogenous quinary heterocyclic radical or replacement (specifically seeing group shown in formula III or the formula IV):
Wherein, R
5～R
9Independently be selected from respectively: H, C
1～C
4Alkoxyl group, C
1～C
4Fluoroalkoxy, halogen (F, Cl, Br or I), nitro (NO
2) or formic acid carbalkoxy (as: COOCH
3(methyl-formiate base) etc.) in a kind of, or R
5～R
9Two of middle arbitrary neighborhoods be combined as the divalence phenyl or
(described divalence phenyl or
With the female ring phenyl be the relation of " also "), all the other are H,
R
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C
1～C
4Phenyl or naphthyl (phenyl of described divalence, C that alkoxyl group replaces
1～C
4The phenyl or naphthyl that alkoxyl group replaces is the relation of " also " with nitrogenous five-membered ring (female ring)), all the other are
And R
10～R
13In have at least one to be
Another object of the present invention is, disclose a kind of purposes of above-mentioned naphthalimide derivative (compound shown in the formula I or its at pharmacologically acceptable salts), be naphthalimide derivative provided by the present invention for the preparation of the application in the medicine of the treatment disease relevant with human beta-N-acetylhexosaminidase, in other words, naphthalimide derivative provided by the present invention is as the application of human beta-N-acetylhexosaminidase inhibitor.
Embodiment
In preferred technical scheme of the present invention, R
1Be H, C
1～C
2Alkoxyl group, Cl, Br, I or
R wherein
3Independently be selected from respectively C with R4
1～C
2A kind of in the alkyl;
Preferred technical scheme is: R
1Be H, methoxyl group (CH
3O-), the amino (N (CH of Br or dimethyl replacement
3)
2).
In another preferred technical scheme of the present invention, R
2Be H, or hydroxyl (OH) or amino (NH
2) C that replaces
1～C
2Alkyl.
In a further preferred technical solution of the present invention, R
2Be group shown in the formula II, and A is group shown in the formula III,
R wherein
5～R
9Independently be selected from respectively: H, C
1～C
2Alkoxyl group, C
1～C
2Fluoroalkoxy, halogen (F, Cl, Br or I), nitro (NO
2) or-COOCH
3In a kind of,
Or
Among R5～R9 two of arbitrary neighborhoods be combined as the divalence phenyl or
(described divalence phenyl or
With the female ring phenyl be the relation of " also "), all the other are H;
Preferred technical scheme is: R
2Be group shown in the formula II, and A is group shown in the formula III,
R wherein
5～R
9Independently be selected from respectively: H, methoxyl group, trifluoromethoxy, Cl ,-NO
2Or-COOCH
3In a kind of, or
R
5～R
9Two of middle arbitrary neighborhoods be combined as the divalence phenyl or
(described divalence phenyl or
With the female ring phenyl be the relation of " also "), all the other are H.
In a further preferred technical solution of the present invention, R
2Be group shown in the formula II, and A is group shown in the formula IV,
R wherein
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C
1～C
2Phenyl or naphthyl (phenyl of described divalence, C that alkoxyl group replaces
1～C
2The phenyl or naphthyl that alkoxyl group replaces is the relation of " also " with nitrogenous five-membered ring (female ring)), all the other are
And R
10～R
13In have at least one to be
Preferred technical scheme is: R
2Be group shown in the formula II, and A is group shown in the formula IV,
R wherein
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, the phenyl or naphthyl (phenyl of described divalence, the phenyl or naphthyl of methoxy substitution and nitrogenous five-membered ring (female ring) are the relation of " also ") of methoxy substitution, all the other are
And R
10～R
13In have at least one to be
In another preferred technical scheme of the present invention, m is 0,1,2 or 3.
In sum, the R of the present invention's recommendation
2Be selected from the following groups a kind of:
In addition, the present invention also provides the method for compound shown in a kind of preparation formula I, its key step (synthesis strategy) is: with 1,8-naphthalene acid anhydride or derivatives thereof (compound shown in the formula V) is raw material, compound shown in the formula V and corresponding amine through inferior amidate action, are obtained one of target compound (brief note is the A series compound); The compound that has terminal amino group in the A series compound is carried out the alkanamine reaction with a series of compounds with end alkyl bromine again, perhaps form azomethine with a series of benzaldehyde compounds, obtain two (brief note is the B series compound) of target compound through reduction, concrete steps are referring to appended embodiment.
The present invention is further elaborated by the following examples, and these embodiment only are used for explanation the present invention and understand better content of the present invention, the protection domain that it does not limit the present invention in any way.
Embodiment 1
Synthesizing of 2-(2-amino-ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (Al)
In the 25mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (2g, 10.1mmol), 50mL dehydrated alcohol and quadrol (1.35mL, 20.2mmol), mixture heating up back flow reaction 2 hours, react complete after, reduction vaporization falls solvent and excessive quadrol, and thick product obtains faint yellow solid product A 1 (1.8g), productive rate 74% with the dehydrated alcohol recrystallization.
Fusing point: 141-142 ℃.
1H NMR (400MHz, DMSO-d
6): δ=8.34 (d, J=7.6Hz, 2H), 8.31 (d, J=8.0Hz, 2H), 7.75 (dd, J=8.0,7.6Hz, 2H), 4.01 (t, J=6.8Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.62ppm (br, 2H);
13CNMR (100MHz, DMSO-d
6): δ=163.9,134.4,131.5,130.9,127.7,127.4,122.4,43.2,40.2ppm; HRMS-ESI (m/z): calculated value: C
14H
13N
2O
2[M+H]
+, 241.0977; Experimental value, 241.0978.
Embodiment 2
Synthesizing of 2-(2-((2-hydroxyethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A2)
In the 25mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (198mg, 1.00mmol), 10mL dehydrated alcohol and hydroxyethylethylene diamine (140mg, 1.00mmol), mixture heating up back flow reaction 2 hours, react complete after, reduction vaporization falls solvent, and thick product obtains white solid product A2 (241mg), productive rate 85% with the dehydrated alcohol recrystallization.
1H?NMR(CDCl
3，400MHz)：δ＝8.55(d，J＝7.2Hz，2H)，8.17(d，J＝8.0Hz，2H)，7.71(dd，J＝8.0，7.2Hz，2H)，4.32(t，J＝6.0Hz，2H)，3.61(t，J＝4.4Hz，2H)，3.02(t，J＝6.0Hz，2H)，2.84(t，J＝4.4Hz，2H)，2.2ppm(br，2H)；
13C?NMR(100MHz，CDCl
3)：δ＝164.5，134.0，131.5，131.3，128.1，126.9，122.5，61.0，50.9，47.4，40.1ppm.EI?MS(m/e)：285.4(M+1，100).
Embodiment 3
Synthesizing of 2-(2-((2-amino-ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A3)
In the 50mL round-bottomed flask, add successively 1,8-naphthalene acid anhydride (198mg, 1.0mmol), 20mL dehydrated alcohol and 2mL diethylenetriamine (excessive), mixture heating up back flow reaction 2 hours, react complete after, filter, collect filtrate, reduction vaporization falls solvent, washing is used dichloromethane extraction three times, collected organic layer, reduction vaporization falls solvent, obtain white solid, thick product obtains white solid product A3 (189mg), productive rate 67% with the dehydrated alcohol recrystallization.
1H?NMR(CDCl
3，400MHz)：δ＝8.54(d，J＝6.8Hz，2H)，8.17(d，J＝8.0Hz，4H)，7.71(t，J＝7.6Hz，2H)，4.32(t，J＝6.0Hz，2H)，3.01(t，J＝6.4Hz，2H)，2.77ppm(s，4H)；
13C?NMR(100MHz，CDCl
3)：δ＝164.0，133.6，131.2，130.9，127.8，126.6，122.2，51.8，47.2，41.4，39.7ppm.EIMS(m/e)：284.6(M+1，100).
Embodiment 4
Synthesizing of 2-(2-amino-ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A4)
The quadrol (165mg, 1.0mmol) of monolateral Boc protection joins 4-nitro-1, in the 10mL ethanolic soln of 8-naphthalene acid anhydride (125mg, 0.5mmol).This mixture return stirring 3 hours, raw material dissolves fully.Question response liquid is down to room temperature, filters, and filtration cakes torrefaction obtains yellow solid 200mg, productive rate 100%.
1H?NMR(400MHz，CDCl
3)：δ＝8.83(d，J＝8.0Hz，1H)，8.74(d，J＝8.0Hz，1H)，8.70(d，J＝8.0Hz，1H)，8.41(d，J＝8.0Hz，1H)，7.99(dd，J＝8.0，8.0Hz，1H)，4.93(br，1H)，4.38(t，J＝5.6Hz，2H)，3.50-3.60(m，2H)，1.25(s，9H)；
13C?NMR(100MHz，CDCl3)：δ＝163.6，162.8，156.1，149.6，132.5，129.9，129.8，129.3，129.2，126.9，123.8，123.7，122.9，79.3，40.5，39.2，28.2ppm.
Getting above-mentioned yellow solid (50mg, 130 μ mol) is mixed among 15mL methyl alcohol and the 2mLDMF with salt of wormwood (100mg, 725 μ mol).This mixture heating up to 60 ℃ stirred 4 hours.Suction filtration while hot, the filtrate decompression evaporate to dryness.(elutriant: DCM) separation obtains solid 30mg, productive rate 62% to thick product silica gel column chromatography.
The 2mL trifluoroacetic acid joins in the 10mL dichloromethane solution of above-mentioned solid (30mg, 81 μ mol), and stirring at room is after 4 hours, and removal of solvent under reduced pressure obtains light green solid (A4) 22mg, fusing point: 205-206 ℃, productive rate 100%.
1H NMR (400MHz, DMSO-d
6): δ=8.54 (dd, J=1.2,8.4Hz, 1H), 8.49 (dd, J=1.2,7.6Hz, 1H), 8.44 (d, J=8.4Hz, 1H), 7.95 (br, 2H), 7.82 (dd, J=7.6,8.4Hz, 1H), 7.32 (d, J=8.4Hz, 1H), (4.30 t, J=6.0Hz, 2H), 4.14 (s, 3H), 3.16 (t, J=6.0Hz, 2H);
13C NMR (100MHz, DMSO-d
6): δ=164.7,163.9,160.9,133.7,131.4,129.2,128.8,126.8,123.2,122.6,114.9,106.7,57.1,38.1,37.8ppm; HRMS-ESI (m/z): calculated value C
15H
15N
2O
3[M+H]
+, 271.1083; Experimental value, 271.1092.
Embodiment 5
Synthesizing of 2-(2-amino-ethyl)-6-dimethyl amido-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A5)
The quadrol (165mg, 1.0mmol) of monolateral Boc protection joins 4-nitro-1, in the 10mL ethanolic soln of 8-naphthalene acid anhydride (125mg, 0.5mmo1).This mixture return stirring 3 hours, raw material dissolves fully.Question response liquid is down to room temperature, filters, and filtration cakes torrefaction obtains yellow solid 200mg, productive rate 100%.
1H?NMR(400MHz，CDCl
3)：δ＝8.83(d，J＝8.0Hz，1H)，8.74(d，J＝8.0Hz，1H)，8.70(d，J＝8.0Hz，1H)，8.41(d，J＝8.0Hz，1H)，7.99(dd，J＝8.0，8.0Hz，1H)，4.93(br，1H)，4.38(t，J＝5.6Hz，2H)，3.50-3.60(m，2H)，1.25(s，9H)；
13C?NMR(100MHz，CDCl
3)：δ＝163.6，162.8，156.1，149.6，132.5，129.9，129.8，129.3，129.2，126.9，123.8，123.7，122.9，79.3，40.5，39.2，28.2pp?m.
Getting above-mentioned yellow solid (50mg, 130 μ mol) joins in the mixing solutions that 2mL DMF and 10mL 40% dimethylamine agueous solution form.This mixture stirring at room is after 12 hours, and all solvents are removed in decompression.Thick product silica gel column chromatography (elutriant: methylene chloride/methanol 40: 1 (v/v)) separates and obtains solid 30mg, productive rate: 60%.
The 2mL trifluoroacetic acid joins in the 10mL dichloromethane solution of above-mentioned solid (30mg, 80 μ mol), and stirring at room is after 4 hours, and removal of solvent under reduced pressure obtains orange solid (A5) 22mg, fusing point: 172-174 ℃, productive rate 99%.
1H?NMR(400MHz，DMSO-d
6)：δ＝8.53(d，J＝8.4Hz，1H)，8.46(d，J＝7.6Hz，1H)，8.34(d，J＝8.0Hz，1H)，7.99(br，2H)，7.75(dd，J＝7.6，8.4Hz，1H)，7.22(d，J＝8.0Hz，1H)，4.30(t，J＝6.0Hz，2H)，3.15(t，J＝6.0Hz，2H)，3.11(s，3H)，3.09ppm(s，3H)；
13C NMR (100MHz, DMSO-d
6): δ=164.8,164.0,157.2,132.7,132.1,131.0,130.3,125.4,124.6,123.0,113.9,113.3,44.9,38.2,37.7ppm; HRMS-ESI (m/z): calculated value C
16H
18N
3O
2[M+H]
+, 284.1399; Experimental value, 284.1399.
Embodiment 6
Synthesizing of 2-(2-amino-ethyl)-6-bromo-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (A6)
Divided by 4-nitro-1,1 in the 8-naphthalene acid anhydride alternative embodiment 1, outside the 8-naphthalene acid anhydride, other condition is identical with embodiment 1 with step, obtains compd A 6, white solid, fusing point: 151-152 ℃, productive rate 70%.
1H NMR (400MHz, DMSO-d
6): δ=8.53 (d, J=8.4Hz, 1H), 8.49 (d, J=7.6Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 8.18 (d, J=8.0Hz, 1H), (7.96 dd, J=7.6,8.4Hz, 1H), (4.07 t, J=6.8Hz, 2H), 2.85 (t, J=6.8Hz, 2H), 2.51ppm (br, 2H);
13C NMR (100MHz, DMSO-d6): δ=163.6,163.5,132.9,131.9,131.8,131.3,130.2,129.4,129.2,128.8,123.4,122.6,42.9,39.9ppm; HRMS-ESI (m/z): calculated value C
14H
12N
2O
2Br[M+H]
+, 319.0082; Experimental value, 319.0079.
Embodiment 7
Synthesizing of 2-(2-((2-(4-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B1)
In the 50mL round-bottomed flask, add successively compd A 1 (450mg, 1.87mmol), the 20mL acetonitrile; 1-(2-bromine oxethyl)-4-anisole (430mg, 1.87mmol) and salt of wormwood (530mg, 3.75mmol); under the argon shield, back flow reaction 12 hours.React complete after, cooling is filtered, removal of solvent under reduced pressure, thick product silica gel column chromatography (CH
2Cl
2/ CH
3OH, 30: 1, v/v) obtain faint yellow solid product B 1 (400mg), fusing point: 107-109 ℃, productive rate 54%.
1H NMR (400MHz, CDCl
3): δ=8.61 (d, J=7.6Hz, 2H), 8.22 (d, J=8.0Hz, 2H), 7.77 (dd, J=7.6,8.0Hz, 2H), 6.86-6.76 (m, 4H), (4.40 t, J=6.4Hz, 2H), 4.03 (t, J=5.2Hz, 2H), 3.77 (s, 3H), (3.16-3.06 m, 4H), 1.97ppm (br, 1H);
13C NMR (100MHz, CDCl
3): δ=164.0,153.7,152.9,133.7,131.3,127.8,126.7,122.3,115.4,114.5,68.0,55.6,48.6,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
23H
23N
2O
4[M+H]
+, 391.1658; Experimental value, 391.1656.
Embodiment 8
Synthesizing of 2-(2-((2-(3-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B2)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-3-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain faint yellow solid (compd B 2), fusing point 79-80 ℃, productive rate 50%.
1H?NMR(400MHz，CDCl
3)：δ＝8.58(d，J＝7.2Hz，2H)，8.19(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，7.13(t，J＝8.0Hz，1H)，6.52-6.42(m，3H)，4.37(t，J＝6.4Hz，2H)，4.05(t，J＝5.2Hz，2H)，3.77(s，3H)，3.14-3.06(m，4H)，1.93ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,160.7,160.1,133.9,131.6,131.2,129.8,128.2,126.9,122.6,106.6,106.5,100.9,67.3,55.2,48.5,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
23H
23N
2O
4[M+H]
+, 391.1658; Experimental value, 391.1654.
Embodiment 9
Synthesizing of 2-(2-((2-(2-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B3)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-2-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain faint yellow solid (compd B 3), fusing point 116-118 ℃, productive rate 65%.
1H?NMR(400MHz，CDCl
3)：δ＝8.56(d，J＝7.6Hz，2H)，8.17(d，J＝8.0Hz，2H)，7.72(dd，J＝7.6，8.0Hz，2H)，6.88(m，4H)，4.36(t，J＝6.8Hz，2H)，4.12(t，J＝5.2Hz，2H)，3.81(s，3H)，3.13(t，J＝5.2Hz，2H)，3.08(t，J＝6.8Hz，2H)，1.89ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.3,149.7,148.4,133.9,131.5,131.2,128.1,128.9,122.6,121.4,120.8,114.1,111.9,68.8,56.8,48.5,47.4,40.0ppm; HRMS-ESI (m/z): calculated value C
23H
23N
2O
4[M+H]
+, 391.1658; Experimental value, 391.1653.
Embodiment 10
Synthesizing of 2-(2-((2-(4-anisole sulfenyl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B4)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine ethylmercapto group)-4-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtains faint yellow solid (compd B 4), productive rate 55%.
1H NMR (400MHz, CDCl
3): δ=8.61 (d, J=7.2Hz, 2H), 8.22 (d, J=8.4Hz, 2H), (7.77 dd, J=7.2,8.4Hz, 2H), 7.35 (d, J=8.8Hz, 2H), 6.81 (d, J=8.8Hz, 2H), 4.34 (t, J=6.4Hz, 2H), 3.79 (s, 3H), 3.01 (t, J=6.4Hz, 2H), 2.97 (t, J=6.0Hz, 2H), (2.88 t, J=6.0Hz, 2H), 1.85ppm (br, 1H);
13C NMR (100MHz, CDCl
3): δ=164.2,158.9,133.8,133.3,131.4,131.1,128.0,126.8,125.8,122.5,114.5,55.3,48.0,47.1,40.0,36.0ppm; HRMS-ESI (m/z): calculated value C
23H
23N
2O
3S[M+H]
+, 407.1429; Experimental value, 407.1429.
Embodiment 11
Synthesizing of 2-(2-((3-(4-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B5)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine propoxy-)-4-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain faint yellow solid (compd B 5), fusing point 110-111 ℃, productive rate 72%.
1H?NMR(400MHz，CDCl
3)：δ＝8.59(d，J＝7.6Hz，2H)，8.21(d，J＝8.0Hz，2H)，6.78(m，4H)，4.38(t，J＝6.4Hz，2H)，3.97(t，J＝6.4Hz，2H)，3.77(s，3H)，3.05(t，J＝6.4Hz，2H)，2.90(t，J＝6.4Hz，2H)，1.96(tt，J＝6.4，6.4Hz，2H)，1.75ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,153.6,153.1,134.0,131.6,131.3,128.2,126.9,122.6,115.3,114.5,67.0,55.7,47.7,46.7,40.0,29.7ppm; HRMS-ESI (m/z): calculated value C
24H
25N
2O
4[M+H]
+, 405.1814; Experimental value, 405.1812.
Embodiment 12
Synthesizing of 2-(2-((3-(3-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B6)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine propoxy-)-3-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain faint yellow solid (compound B-26), fusing point: 85-86 ℃, productive rate 70%.
1H?NMR(400MHz，CDCl
3)：δ＝8.57(d，J＝7.6Hz，2H)，8.19(d，J＝8.4Hz，2H)，7.73(dd，J＝7.6，8.4Hz，2H)，7.12(dd，J＝7.6，8.0Hz，1H)，6.50-6.42(m，3H)，4.36(t，J＝6.4Hz，2H)，4.00(t，J＝6.4Hz，2H)，3.76(s，3H)，3.05(t，J＝6.4Hz，2H)，2.90(t，J＝6.8Hz，2H)，1.96(dt，J＝6.4，6.8Hz，2H)，1.54ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,160.8,160.2,133.9,131.6,131.2,129.7,128.2,126.9,122.6,106.6,106.3,100.9,66.3,55.2,47.7,46.6,40.0,29.7ppm; HRMS-ESI (m/z): calculated value C
24H
25N
2O
4[M+H]
+, 405.1814; Experimental value, 405.1818.
Embodiment 13
Synthesizing of 2-(2-((3-(4-anisole sulfenyl) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B7)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(3-bromine rosickyite base)-4-anisole alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain faint yellow solid (compd B 7), fusing point: 97-98 ℃, productive rate 65%.
1H?NMR(400MHz，CDCl
3)：δ＝8.56(d，J＝7.6Hz，2H)，8.18(d，J＝8.0Hz，2H)，7.72(dd，J＝7.6，8.0Hz，2H)，7.30(d，J＝8.8Hz，2H)，6.80(d，J＝8.8Hz，2H)，4.31(t，J＝6.4Hz，2H)，3.77(s，3H)，2.98(t，J＝6.4Hz，2H)，2.84(t，7.2Hz，2H)，2.78(t，J＝6.8Hz，2H)，1.74(dt，J＝6.8，7.2Hz，2H)，1.35ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.3,158.7,133.9,133.0,131.5,131.2,128.1,126.9,126.6,122.6,114.5,55.3,48.3,47.740.0,33.5,29.7ppm; HRMS-ESI (m/z): calculated value C
24H
25N
2O
3S[M+H]
+, 421.1586; Experimental value 421.1583.
Embodiment 14
Synthesizing of 2-(2-((2-(benzo [d] [1,3] methylene-dioxy-5-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B8)
Beyond 1-(2-bromine oxethyl)-4-anisole in Compound C 1 alternative embodiment 7, other condition is identical with embodiment 7 with step, obtains yellow solid (compd B 8), and fusing point: 119-120 ℃, productive rate 44%.
1H?NMR(400MHz，CDCl
3)：δ＝8.61(d，J＝7.6Hz，2H)，8.22(d，J＝8.0Hz，2H)，7.77(dd，J＝7.6，8.0Hz，2H)，6.65(d，J＝8.4Hz，1H)，6.46(d，J＝1.2Hz，1H)，6.29(dd，J＝1.2，8.4Hz，1H)，5.91(s，2H)，4.39(t，J＝6.4Hz，2H)，3.99(t，J＝5.2Hz，2H)，3.18-.3.00(m，4H)，1.92ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,154.3,148.1,141.6,134.0,131.6,131.3,128.2,126.9,122.6,107.8,105.6,101.1,98.1,68.2,48.5,47.4 39.9ppm; HRMS-ESI (m/z): calculated value C
23H
21N
2O
5[M+H]
+, 405.1450; Experimental value 405.1455.
Embodiment 15
Synthesizing of 2-(2-((2-(3,4-dimethoxy phenoxy group) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B9)
Divided by 1-(2-bromine oxethyl)-3, beyond 1-in the 4-dimethoxy benzene alternative embodiment 7 (2-bromine oxethyl)-4-anisole, other condition is identical with embodiment 7 with step, obtains yellow solid (compd B 9), fusing point: 119-121 ℃, productive rate 45%.
1H NMR (400MHz, CDCl
3): δ=8.59 (d, J=7.6Hz, 2H), 8.20 (d, J=8.0Hz, 2H), (7.74 dd, J=7.6,8.0Hz, 2H), 6.73 (d, J=8.8Hz, 1H), 6.51 (d, J=2.4Hz, 1H), 6.37 (dd, J=2.4,8.8Hz, 1H), 4.40 (t, J=6.4Hz, 2H), 4.04 (t, J=5.2Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.15-3.08 (m, 4H), 2.39 (br, 1H);
13C NMR (100MHz, CDCl
3): δ=164.4,153.5,149.8,143.6,133.9,131.6,131.2,128.2,126.9,122.6,111.9,103.9,101.0,67.8,56.5,55.8,48.5,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
24H
25N
2O
5[M+H]
+, 421.1763; Experimental value 421.1760.
Embodiment 16
Synthesizing of 2-(2-((2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B10)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-Trifluoromethyl phenyl ether alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain yellow solid (compound B-11 0), fusing point: 93-94 ℃, productive rate 50%.
1H?NMR(400MHz，CDCl
3)：δ＝8.62(d，J＝7.6Hz，2H)，8.23(d，J＝8.4Hz，2H)，7.77(dd，J＝7.6，8.4Hz，2H)，7.10(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，2H)，4.40(t，J＝6.4Hz，2H)，4.05(t，J＝5.2Hz，2H)，3.15-3.05(m，4H)，1.90ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,157.4,142.7,134.0,131.6,131.3,128.2,126.9,122.6,122.3,115.3,67.9,48.3,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
23H
20N
2O
4F
3[M+H]
+, 445.1375; Experimental value 445.1375.
Embodiment 17
4-(synthesizing of 2-((2-(1,3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) oxyethyl group) methyl benzoate (B11)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-methyl-formiate base benzene alternative embodiment 7, other condition is identical with embodiment 7 with step, obtain white solid (compound B-11 1), fusing point: 107-109 ℃, productive rate 53%.
1H?NMR(400MHz，CDCl
3)：δ＝8.61(d，J＝8.0Hz，2H)，8.22(d，J＝8.4Hz，2H)，7.93(d，J＝7.2Hz，2H)，7.75(dd，J＝8.0，8.4Hz，2H)，6.87(d，J＝8.4Hz，2H)，4.39(t，J＝6.4Hz，2H)，4.12(t，J＝5.2Hz，2H)，3.89(s，3H)，3.15-3.08(m，4H)，1.94(s，1H)；
13C NMR (100MHz, CDCl
3): δ=166.8,164.4,162.6,134.0,131.6,131.5,131.3,128.2,126.9,122.6,114.1,67.5,51.8,48.2,47.4,39.8ppm; HRMS-ESI (m/z): calculated value C
24H
23N
2O
5[M+H]
+, 419.1607; Experimental value 419.1607.
Embodiment 18
Synthesizing of 2-(2-((2-(4-chlorophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B12)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-4-chlorobenzene alternative embodiment 7, other condition is identical with embodiment 7 with step, obtains yellow solid (compound B-11 2), fusing point: 106-107 ℃.
1H?NMR(400MHz，CDCl
3)：δ＝8.58(d，J＝7.2Hz，2H)，8.20(d，J＝8.4Hz，2H)，7.74(dd，J＝7.2，8.4Hz，2H)，7.16(d，J＝8.8Hz，2H)，6.77(d，J＝8.8Hz，2H)，4.37(t，J＝6.4Hz，2H)，4.01(t，J＝5.2Hz，2H)，3.11-3.05(m，4H)，1.77ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,157.5,134.0,131.6,131.2,129.2,128.2,126.9,125.5,122.6,115.7,67.7,48.3,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
22H
10N
2O
3Cl[M+H]
+, 395.1162; Experimental value 395.1154.
Embodiment 19
Synthesizing of 2-(2-((2-(4-nitrophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B13)
1H?NMR(400MHz，CDCl
3)：δ＝8.59(d，J＝7.6Hz，2H)，8.22(d，J＝8.4Hz，2H)，8.11(d，J＝9.2Hz，2H)，7.76(dd，J＝7.6，8.4Hz，2H)，6.89(d，J＝9.2Hz，2H)，4.38(t，J＝6.4Hz，2H)，4.13(t，J＝5.2Hz，2H)，3.16-3.08(m，4H)，1.69ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,163.9,141.4,134.0,131.6,131.3,128.2,126.9,125.8,122.5,114.4,68.4,48.0,47.4,39.9ppm; HRMS-ESI (m/z): calculated value C
22H
20N
3O
5[M+H]
+, 406.1403; Experimental value 406.1404.
Embodiment 20
Synthesizing of 2-(2-((2-((4-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B14)
In the 25mL round-bottomed flask, add successively 1-bromo-4-anisole (5g, 26.7mmol), cuprous iodide (510mg, 2.7mmol), L-PROLINE (615mg, 5.4mmol) and salt of wormwood (7.4g, 53.5mmol), oxyethylamine (4.8mL, 80.2mmol) and DMSO (20mL).After degassed, under this mixture argon shield, 60 ℃ stir 24 hours complete to raw material reaction.Reactant imports in the 100mL water, ethyl acetate (100mL) extraction three times.Organic phase merges, and drying, evaporated under reduced pressure obtain thick product.Separate (CH through silica gel column chromatography
2Cl
2/ CH
3OH 30: 1, v/v) obtains red oil (3.5g), productive rate 78%.
Under the room temperature, Tetrabutyl amonium bromide is joined 2,3-, two chloro-5, the dichloromethane solution of 6-dicyan para benzoquinone (48mg, 2.1mmol) and triphenylphosphine (562mg, 2.1mmol).Get above-mentioned red oil (240mg, 1.4mmol) and add this mixture, solution changes scarlet into by yellow at once.After the stirring at room 30 minutes, the direct evaporated under reduced pressure of reaction solution, thick product silica gel column chromatography separation obtains corresponding brominated product, yellow oil (270mg), productive rate 82%.
In the 50mL round-bottomed flask, add successively compd A 1 (450mg, 1.87mmol), the 20mL acetonitrile; N-(2-bromotrifluoromethane)-4-anisidine (431mg, 1.87mmol) and salt of wormwood (518mg, 3.75mmol); under the argon shield, back flow reaction 12 hours.React complete after, cooling is filtered, removal of solvent under reduced pressure, thick product column chromatography (CH
2Cl
2/ CH
3OH 30: 1, v/v) obtains 405mg red solid product (compound B-11 4), fusing point: 100-101 ℃, productive rate 55%.
1H?NMR(400MHz，CDCl
3)：δ＝8.58(d，J＝7.2Hz，2H)，8.20(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，6.69(d，J＝9.2Hz，2H)，6.50(d，J＝9.2Hz，2H)，4.41(t，J＝6.4Hz，2H)，3.72(s，3H)，3.20(t，J＝6.0Hz，2H)，3.13(t，J＝6.4Hz，2H)，3.04ppm(t，J＝6.0Hz，2H)；
13C NMR (100MHz, CDCl
3): δ=164.5,152.0,142.6,134.1,134.0,131.6,131.4,131.3,128.2,126.9,126.8,122.5,119.3,114.8,114.2,113.9,55.8,48.1,47.2,43.8,39.2ppm; HRMS-ESI (m/z): calculated value C
23H
24N
3O
3[M+H]
+, 290.1818; Experimental value, 290.1819.
Embodiment 21
Synthesizing of 2-(2-((2-((3-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B15)
Beyond 1-bromo-4-anisole in the 1-bromo-3-anisole alternative embodiment 20, other condition is identical with embodiment 20 with step, obtains yellow solid (compound B-11 5), and fusing point: 148-149 ℃, productive rate 70%.
1H?NMR(400MHz，CDCl
3)：δ＝8.60(dd，J＝0.8，7.6Hz，2H)，8.21(dd，J＝0.8，8.4Hz，2H)，7.75(dd，J＝7.6，8.4Hz，2H)，7.01(dd，J＝8.0，8.4Hz，1H)，6.23(dd，J＝2.0，8.0Hz，1H)，6.14(dd，J＝1.6，8.4Hz，1H)，6.11(dd，J＝1.6，2.0Hz，1H)，4.36(t，J＝6.4Hz，2H)，4.22(br，1H)，3.75(s，3H)，3.17(m，2H)，3.06(t，J＝6.4Hz，2H)，2.98(t，J＝5.6Hz，2H)，1.46ppm(br，1H)；
13C NMR (100MHz, CDCl3): δ=164.5,160.7,150.0,134.0,131.6,131.3,129.8,128.2,126.9,122.6,105.9,102.4,98.6,55.0,48.1,47.4,43.5,39.9ppm; HRMS-ESI (m/z): calculated value C
23H
24N
3O
3[M+H]
+, 290.1818; Experimental value, 290.1819.
Embodiment 22
Synthesizing of 2-(2-((2-((2,4-Dimethoxyphenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B16)
Divided by 1-bromo-2, beyond the 1-bromo-4-anisole, other condition is identical with embodiment 20 with step in the 3-dimethoxy benzene alternative embodiment 20, obtains red solid (compound B-11 6), and fusing point: 96-97 ℃, productive rate 68%.
1H?NMR(400MHz，CDCl
3)：δ＝8.59(d，J＝7.2Hz，2H)，8.21(d，J＝7.6Hz，2H)，7.75(dd，J＝7.2，7.6Hz，2H)，6.52(d，J＝8.4Hz，1H)，6.40-6.35(m，2H)，4.37(t，J＝6.8Hz，2H)，3.75(s，3H)，3.68(s，3H)，3.20(t，J＝6.0Hz，2H)，3.07(t，J＝6.8Hz，2H)，3.00ppm(t，J＝6.0Hz，2H)；
13C NMR (100MHz, CDCl
3): δ=164.4,151.8,148.1,133.9,132.8,131.6,131.2,128.2,126.9,122.7,110.3,103.8,99.2,55.8,55.3,48.6,47.5,44.2,40.0ppm; HRMS-ESI (m/z): calculated value C
24H
26N
3O
4[M+H]
+, 420.1923; Experimental value 420.1922.
Embodiment 23
Synthesizing of 2-(2-((4-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B17)
In the 50mL round-bottomed flask, add compd A 1 (500mg, 2.1mmol), 4-methoxybenzaldehyde (280mg, 2.1mmol) and 20mL methyl alcohol.This mixture stirred overnight at room temperature, suction filtration, the filter cake IR bake is dry, obtains white solid.
Again sodium triacetoxy borohydride (530mg, 2.5mmol) is joined the 20mL1 of above-mentioned solid and acetic acid (0.12mL, 2.1mmol), the 2-dichloroethane solution.Pour into after the stirred overnight at room temperature in the 50mL water, methylene dichloride (50mL) extraction three times merges organic phase, dry organic phase, and pressurization is steamed except organic solvent, and resistates separates (CH through silica gel column chromatography
2Cl
2/ CH
3OH 30: 1, v/v) obtains pale solid (compound B-11 7) 380mg, fusing point: 142-143 ℃, productive rate 50%.
1H NMR (400MHz, CDCl
3): δ=8.59 (d, J=7.2Hz, 2H), 8.22 (d, J=7.6Hz, 2H), 7.76 (dd, J=7.2,7.6Hz, 2H), (7.26 d, J=8.8Hz, 2H), 6.80 (d, J=8.8Hz, 2H), 3.39 (t, J=6.4Hz, 2H), 3.85 (s, 2H), 3.76 (s, 3H), 3.06 (t, J=6.4Hz, 2H), 1.49ppm (br, 1H);
13C NMR (100MHz, CDCl
3): δ=164.4,158.5,133.9,132.6,131.6,131.2,129.3,128.2,126.9,122.7,113.7,55.2,52.9,47.0,40.0ppm; HRMS-ESI (m/z): calculated value C
22H
21N
2O
3[M+H]
+, 361.1552; Experimental value, 361.1551.
Embodiment 24
Synthesizing of 2-(2-((3-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B18)
Beyond 4-methoxybenzaldehyde in the m-methoxybenzaldehyde alternative embodiment 23, other condition is identical with embodiment 23 with step, obtains white solid (compound B-11 8).Fusing point: 110-112 ℃, productive rate 65%.
1H NMR (400MHz, CDCl
3): δ=8.58 (d, J=7.2Hz, 2H), 8.20 (d, J=8.0Hz, 2H), 7.74 (dd, J=7.2,8.0Hz, 2H), (7.17 t, J=8.0Hz, 1H), 7.91-6.86 (m, 2H), (6.76-6.71 m, 1H), 4.38 (t, J=6.4Hz, 2H), (3.85 s, 2H), 3.75 (s, 3H), 3.05 (t, J=6.4Hz, 2H), 1.65ppm (br, 1H);
13C NMR (100MHz, CDCl
3): δ=164.4,159.7,142.1,133.9,131.6,131.2,129.3,128.2,126.9,122.7,120.4,113.3,112.6,55.1,53.5,47.1,40.0ppm; HRMS-ESI (m/z): calculated value C
22H
21N
2O
3[M+H]
+, 361.1552; Experimental value 361.1554.
Embodiment 25
Synthesizing of 2-(2-((3,4-Dimethoxyphenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B19)
Beyond 4-methoxybenzaldehyde in the Veratraldehyde alternative embodiment 23, other condition is identical with embodiment 23 with step, obtains white solid (compound B-11 9).Fusing point: 142-143 ℃, productive rate 62%.
1H?NMR(400MHz，CDCl
3)：δ＝8.59(d，J＝7.2Hz，2H)，8.21(d，J＝8.0Hz，2H)，7.75(dd，J＝7.2，8.0Hz，2H)，6.88(d，J＝1.6Hz，1H)，6.83(dd，J＝1.6，8.4Hz，1H)，6.75(d，J＝8.4Hz，1H)，4.38(t，J＝6.4Hz，2H)，3.83(s，3H)，3.81(s，2H)，3.80(s，3H)，3.04(t，J＝6.4Hz，2H)，1.76ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,148.9,147.9,133.9,133.0,131.6,131.2,128.2,126.9,122.6,120.2,111.4,110.9,55.9,55.7,53.2,46.9,39.9ppm; HRMS-ESI (m/z): calculated value C
23H
23N
2O
4[M+H]
+, 391.1658; Experimental value 391.1656.
Embodiment 26
Synthesizing of 2-(2-((2-(1,3-dioxoisoindolin) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B20)
With phthalic imidine (1.0g, 6.8mmol) 10mL DMF solution join and be equipped with 1,2-ethylene dibromide (3mL, 34.0mmol), in the 50mL round-bottomed flask of salt of wormwood (1.9g, 14.0mmol) and 20mLDMF, after the stirring at room 2 hours, pressure reducing and steaming is 20mLDMF approximately, and surplus materials is poured in the 100mL water, methylene dichloride 100mL extraction three times, merge organic phase, drying is filtered, and removes organic solvent in the gained filtrate under reduced pressure, resistates separates (AcOEt/PE through silica gel column chromatography, 1: 5, v/v) obtain white solid (Compound C 2) 750mg, productive rate: 43%;
Compound C 2 and compd A 1 are pressed the condition described in the embodiment 7 and step reaction, obtain white solid (compd B 20), fusing point: 172-174 ℃, productive rate 70%.
1H NMR (400MHz, CDCl
3): δ=8.49 (d, J=7.2Hz, 2H), 8.21 (d, J=8.0Hz, 2H), 7.72 (dd, J=7.2,8.0Hz, 2H), (7.63 s, 4H), 4.32 (t, J=6.0Hz, 2H), 3.80 (t, J=6.0Hz, 2H), (3.07 t, J=6.0Hz, 2H), 3.02 (t, J=6.0Hz, 2H), 1.59ppm (s, 1H);
13C NMR (100MHz, CDCl
3): δ=168.4,164.4,133.8,133.6,132.1,126.9,123.0,122.7,47.4,47.2,39.7,37.6ppm; HRMS-ESI (m/z): calculated value C
24H
19N
3O
4[M+H]
+, 414.1454; Experimental value 414.1456.
Embodiment 27
2-(synthesizing of 2-((2-(2-oxygen benzo [cd] indoles-1 (1H)-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B21):
Outside phthalic imidine in Compound C 3 alternate embodiments 26, other condition is identical with embodiment 26 with step, obtains yellow look solid (compd B 21), productive rate 62%.
1H?NMR(400MHz，CDCl
3)：δ＝8.64(d，J＝7.2Hz，2H)，8.21(d，J＝8.0Hz，2H)，8.11(d，J＝7.2Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.76(dd，J＝8.0，7.6Hz，2H)，7.62(t，J＝7.6Hz，1H)，7.42(t，J＝7.6Hz，1H)，7.34(d，J＝8.4Hz，1H)，6.69(d，J＝7.2Hz，1H)，4.70(t，J＝7.2Hz，2H)，4.22(t，J＝7.2Hz，2H)，4.08(t，J＝4.4Hz，2H)，3.93(t，J＝4.4Hz，2H)，1.65ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,158.4,142.7,133.9,131.6,131.3,130.1,128.9,128.8,128.4,128.2,126.9,126.3,125.5,125.2,122.7,117.2,101.6,63.2,47.7,45.7,41.2ppm; HRMS-ESI (m/z): calculated value C
27H
22N
3O
3[M+H]
+, 436.1661; Experimental value 436.1659.
Embodiment 28
N-(synthesizing of 2-((2-(1,3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) ethyl)-4-methoxy benzamide (B22)
Under 0 ℃, thionyl chloride (4.8mL, 65.7mmol) is added drop-wise in the 20mL benzole soln of anisic acid (2.0g, 13.2mmol).After the reflux 8 hours, be cooled to room temperature, underpressure distillation goes out desolventizing and excessive thionyl chloride obtains anisoyl chloride, colourless liquid 2.2g.
Get aforesaid liquid 60mg (0.35mmol) and be dissolved in the 10mL methylene dichloride, slowly be added drop-wise to the 10mL dichloromethane solution of compound A-13 (150mg, 0.53mmol) and pyridine (2mL).Stirring at room is after react completely, and reaction solution is poured in the 50mL water, and methylene dichloride 50mL extraction three times merges organic phase, and drying is filtered, and filtrate decompression is steamed desolventize, and resistates separates (CH through silica gel column chromatography
2Cl
2/ CH
3OH 30: 1, v/v), obtains yellow solid (compd B 22) 100mg, productive rate 68%.
1H?NMR(400MHz，CDCl
3)：δ＝8.39(d，J＝6.8Hz，2H)，8.10(d，J＝7.2Hz，2H)，7.65-7.56(m，4H)，7.04(s，1H)，6.70(d，J＝6.4Hz，2H)，4.26(t，J＝6.0Hz，2H)，3.75(s，3H)，3.80(t，J＝6.0Hz，2H)，3.07(t，J＝6.0Hz，2H)，3.02(t，J＝6.0Hz，2H)，1.59ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=167.2,164.4,161.8,133.9,131.4,131.2,128.8,127.9,127.0,126.8,122.3,113.4,77.5,77.4,77.2,76.9,55.3,47.9,47.4,39.7ppm; HRMS-ESI (m/z): calculated value C
24H
24N
3O
4[M+H]
+, 418.1767; Experimental value 418.1770.
Embodiment 29
Synthesizing of 2-(2-((2-(naphthalene-1-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B23)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-(2-bromine oxethyl)-naphthalene alternative embodiment 7, other condition is identical with embodiment 7 with step, obtains white solid (compd B 23), productive rate 65%.
1H?NMR(400MHz，CDCl
3)：δ＝8.51(d，J＝7.2Hz，2H)，8.19(d，J＝8.0Hz，1H)，8.09(d，J＝8.0Hz，2H)，7.72(d，J＝8.0Hz，1H)，7.64(dd，J＝8.0，7.2Hz，2H)，7.42(dt，J＝7.4，1.2Hz，1H)，7.35(m，2H)，7.26(m，1H)，6.74(d，J＝7.6Hz，1H)，4.38(t，J＝6.8Hz，2H)，4.20(t，J＝5.2Hz，2H)，3.22(t，J＝5.2Hz，2H)，3.15(t，J＝6.8Hz，2H)，1.90ppm(br，1H)；
13C NMR (100MHz, CDCl
3): δ=164.4,154.5,134.4,133.9,131.5,131.2,128.1,127.4,126.8,126.3,125.8,125.6,125.1,122.5,122.0,120.3,104.7,67.7,48.5,47.6,40.0ppm; HRMS-ESI (m/z): calculated value C
26H
23N
2O
3[M+H]
+, 411.1709; Experimental value, 411.1722.
Embodiment 30
Synthesizing of 2-(2-((2-(naphthalene-1-is amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B24)
Beyond 1-(2-bromine oxethyl)-4-anisole in 1-((2-bromotrifluoromethane) amino)-naphthalene alternative embodiment 7, other condition is identical with embodiment 7 with step, obtains faint yellow solid (compd B 24), productive rate 50%.
1H NMR (400MHz, CDCl
3): δ=8.56 (d, J=7.2Hz, 2H), 8.15 (d, J=8.0Hz, 1H), (7.69 m, 4H), 7.35 (t, J=7.2Hz, 1H), (7.28 t, J=7.6Hz, 1H), 7.13 (m, 2H), (6.52 d, J=7.6Hz, 1H), 5.01 (br, 1H), (4.39 t, J=6.0Hz, 2H), 3.30 (t, J=4.8Hz, 2H), 3.13 (m, 4H), 1.42ppm (br, 1H);
13CNMR (100MHz, CDCl
3): δ=164.6,143.9,134.2,134.0,131.5,131.3,128.4,128.2,126.9,126.6,125.5,124.3,123.5,122.5,120.1,117.0,104.1,47.9,47.5,43.6,39.9ppm; HRMS-ESI (m/z): calculated value C
26H
24N
3O
2[M+H]
+, 410.1869; Experimental value, 410.1862.
Embodiment 31
Synthesizing of 2-(2-((2-(5-methoxyl group-2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B25)
5-methoxyl group isatin (Compound C 4) (1.0g, 5.64mmol), neopentyl glycol (589mg, 5.64mmol) and tosic acid (49mg, 0.28mmol) mixing are dissolved in the 30mL toluene, are heated to backflow, stir 8 hours.Reaction solution is down to room temperature, filters, and the filtrate decompression evaporate to dryness, (AcOEt/PE 2: 3, v/v) obtains white solid (Compound C 5) 1.25g, productive rate 84% to resistates through the silica gel column chromatography separation.
1H?NMR(400MHz，CDCl
3)：δ＝8.20(s，1H)，7.06(d，J＝2.4Hz，1H)，6.82(dd，J＝2.4，8.0Hz，1H)，6.70(d，J＝8.0Hz，1H)，4.73(d，J＝10.8Hz，2H)，3.80(s，3H)，3.55(d，J＝10.8Hz，2H)，1.43(s，3H)，0.91ppm(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ＝173.7，156.3，133.5，128.4，116.4，110.9，110.4，93.7，71.3，55.9，30.3，23.0，22.1ppm.
Join under sodium hydride (304mg, the 7.60mmol) ice bath in the 10mLDMF solution of Compound C 5 (1.0g, 3.80mmol) in batches.Under 30 ℃ of conditions, stir after 30 minutes, add glycol dibromide (0.66mL, 7.60mmol).Be warming up to 40 ℃, continue to be stirred to and react completely.Reaction solution is poured in the 50mL ethyl acetate, 50mL washing three times.Dry organic phase is filtered, the filtrate decompression evaporate to dryness, and (AcOEt/PE 1: 3, v/v) obtains yellow oil (Compound C 6) 1.3g, productive rate: 92% to resistates through the silica gel column chromatography separation.
1H?NMR(400MHz，CDCl
3)：δ＝7.07(d，J＝2.8Hz，1H)，6.87(dd，J＝2.8，8.4Hz，1H)，6.74(d，J＝8.4Hz，1H)，4.72(d，J＝10.8Hz，2H)，3.99(t，J＝7.2Hz，2H)，3.81(s，3H)，3.55-3.48(m，4H)，1.42(s，3H)，0.89ppm(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ＝171.1，156.6，135.0，127.9，116.0，110.8，109.1，93.3，71.4，55.9，41.2，30.3，27.0，23.0，22.1ppm.
Condition and step reaction with Compound C 6 and compd A 1 are pressed embodiment 7 obtain yellow solid (Compound C 7).Productive rate 55%.
1H?NMR(400MHz，CDCl
3)：δ＝8.55(d，J＝7.2Hz，2H)，8.18(d，J＝7.6Hz，2H)，7.72(dd，J＝7.2，7.6Hz，2H)，7.00(d，J＝1.6Hz，1H)，6.82-6.72(m，2H)，4.67(d，J＝11.2Hz，2H)，4.32(d，J＝6.4Hz，2H)，3.77(s，3H)，3.70(t，J＝6.4Hz，2H)，3.43(d，J＝11.2Hz，2H)，3.06(d，J＝6.4Hz，2H)，2.98(d，J＝6.4Hz，2H)，1.95(s，1H)，1.38(s，3H)，0.83ppm(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ＝171.4，164.3，156.3，135.8，133.9，131.5，131.2，128.1，127.9，126.9，122.6，115.9，110.5，109.5，93.4，71.2，56.9，47.3，46.5，39.7，39.6，30.2，23.0，22.1ppm。
Compound C 7 is joined hydrochloric acid/acetic acid, and (v/v=3: in the mixing solutions 1), stirring at room was slowly poured the saturated solution of sodium bicarbonate into after 10 minutes, dichloromethane extraction three times merges organic phase, drying, filter, the filtrate decompression evaporate to dryness, resistates separates (CH through silica gel column chromatography
3OH/CH
2Cl
2, 30: 1, v/v), obtain red solid (compd B 25) 1.3g, fusing point: 169-170 ℃, productive rate 90%.
1H?NMR(400MHz，CDCl
3)：δ＝8.52(d，J＝7.2Hz，2H)，8.20(d，J＝7.6Hz，2H)，7.74(dd，J＝7.2，7.6Hz，2H)，7.04-6.97(m，2H)，6.95(d，J＝8.0Hz，1H)，4.31(t，J＝6.4Hz，2H)，3.79(t，J＝6.4Hz，2H)，3.76(s，3H)，3.14-3.00(m，4H)，2.31ppm(s，1H)；
13C NMR (100MHz, CDCl
3): δ=183.7,164.4,158.6,156.2,145.1,134.0,131.5,131.3,128.1,126.9,124.6,122.4,117.9,111.6,109.3,55.9,47.4,46.5,40.3,39.4ppm; HRMS-ESI (m/z): calculated value C
25H
22N
3O
5[M+H]
+, 444.1559; Experimental value, 444.1560.
Embodiment 32
Synthesizing of 2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B26)
Outside the Compound C 4 in the Compound C 4a alternative embodiment 31, other condition is identical with embodiment 31 with step, can obtain orange solid (compd B 26).Fusing point: 82-84 ℃.
1H NMR (400MHz, CDCl
3): δ=8.56 (d, J=7.6Hz, 2H), 8.23 (d, J=8.0Hz, 2H), 7.77 (dd, J=7.6,8.0Hz, 2H), (7.51 d, J=7.6Hz, 1H), 7.46 (dd, J=7.2,7.6Hz, 1H), 7.05-6.95 (m, 2H), (4.32 t, J=6.4Hz, 2H), 3.82 (t, J=6.4Hz, 2H), 3.00-3.10ppm (m, 4H);
13C NMR (100MHz, CDCl
3): δ=183.4,164.5,158.5,151.2,138.2,134.0,131.6,131.3,128.2,127.0,125.1,123.4,122.5,117.6,110.5,47.5,46.5,40.5,39.6ppm; HRMS-ESI (m/z): calculated value C
24H
20N
3O
4[M+H]
+, 414.1454; Experimental value 414.1454.
Embodiment 33
Synthesizing of 2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B27)
Beyond compd A 1 in compd A 4 alternative embodiments 32, other condition is identical with embodiment 32 with step, can obtain yellow solid (compd B 27).
1H NMR (400MHz, CDCl
3): δ=8.61-8.51 (m, 2H), 8.50 (d, J=8.4Hz, 1H), 7.70 (dd, J=7.6,8.0Hz, 1H), 7.50 (d, J=7.2Hz, 1H), 7.45 (dd, J=7.6,8.0Hz, 1H), (7.04 d, J=8.0Hz, 1H), 7.02-6.96 (m, 2H), (4.28 t, J=6.0Hz, 2H), 4.14 (s, 3H), (3.80 t, J=6.0Hz, 2H), 3.10-2.97ppm (m, 4H);
13C NMR (100MHz, CDCl
3): δ=183.4,164.8,164.2,161.0,158.5,151.3,138.2,133.6,131.6,129.4,128.8,126.0,125.1,123.5,123.4,122.2,117.6,114.9,110.5,105.2,56.2,47.6,46.5,40.5,39.5ppm; HRMS-ESI (m/z): calculated value C
25H
22N
3O
5(M+H), 444.1559; Experimental value, 444.1564.
Embodiment 34
Synthesizing of 2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-dimethyl amine-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B28)
Beyond compd A 1 in the compound A-45 alternative embodiment 32, other condition is identical with embodiment 32 with step, can obtain red solid (compd B 28).
1H NMR (400MHz, CDCl
3): δ=8.53 (d, J=7.2Hz, 1H), 8.40-8.50 (m, 2H), 7.68 (dd, J=7.6,8.0Hz, 1H), 7.54 (d, J=7.6Hz, 1H), (7.49 dd, J=7.6,8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 7.00-7.40 (m, 2H), 4.31 (t, J=6.0Hz, 2H), 3.85 (t, J=6.0Hz, 2H), (3.14 s, 6H), 3.07ppm (t, J=6.0Hz, 4H);
13C NMR (100MHz, CDCl3): δ=Gp-156-125; HRMS-ESI (m/z): calculated value C
26H
25N
4O
4[M+H]
+, 457.1876; Experimental value, 457.1877.
Embodiment 35
Synthesizing of 2-(2-((2-(2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-bromo-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone (B29)
Beyond compd A 1 in compd A 6 alternative embodiments 32, other condition is identical with embodiment 32 with step, can obtain orange solid (compd B 29), fusing point: 90-92 ℃.
1H NMR (400MHz, CDCl
3): δ=8.65-8.55 (m, 2H), 8.37 (d, J=7.6Hz, 1H), (8.06 d, J=8.0Hz, 1H), 7.87 (dd, 7.6,8.0Hz, 1H), 7.52 (d, J=7.6Hz, 1H), (7.47 dd, J=7.6,8.0Hz, 1H), 7.05-6.95 (m, 2H), 4.31 (t, J=6.0Hz, 2H), 3.81 (t, J=6.4Hz, 2H), 3.10-3.00ppm (m, 4H);
13CNMR (100MHz, CDCl
3): δ=183.4,163.9,158.5,151.2,138.1,133.4,132.1,131.3,131.1,130.7,130.4,129.1,128.1,125.2,123.4,123.0,122.1,117.6,110.4,47.4,46.5,40.5,39.7ppm; HRMS-ESI (m/z): calculated value C
24H
19N
3O
4Br[M+H]
+, 492.0559; Experimental value, 492.0563.
Embodiment 36
Compound provided by the invention is to the inhibition active testing of human N-acetyl hexosaminidase:
All test compounds all are dissolved in the aqueous solution of 20% ethanol, and concentration is 0.1mM.Take M-31850 (Product Name: β-Hexosaminidase Inhibitor) as control compound.Suppressing active testing uses human beta-N-acetylhexosaminidase available from Sigma-Aldrich company (CAS Number:9012-33-3).Enzymic activity test uses substrate (to be abbreviated as 4MU-β-GlcNAc), available from Sigma-Aldrich company as 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide.Probe temperature is 37 ℃.
Test procedure: be preculture 10 minutes in the citrate buffer solution (pH=4.25) of 50mM with the inhibitor of human beta-N-acetylhexosaminidase and different concns in concentration at first; Then add respectively 4MU-β-GlcNAc and be respectively 8 μ M and 16 μ M to final concentration, the initiation enzymatic reaction; Add at last 0.5M sodium carbonate solution 100 μ l termination reactions.Utilize fluorescence spectrophotometer to measure the fluorescence intensity of hydrolysate 4MU, excitation wavelength is 360nm, and emission wavelength is 405nm.Suppressing constant (Ki) utilizes Dixon plots linear regression data to calculate.The results are shown in Table 1.
As shown in Table 1, this type of naphthalimide derivative has obvious inhibition activity to human beta-N-acetylhexosaminidase.Compare known non-glycosyl STRUCTURE DEPRESSION agent M-31850, this compounds can reach better or equal inhibition.Because the clinical toxicity of M-31850, make it can not be as the pharmacological agent relative disease.But the active compound among the present invention is the human beta-N-acetylhexosaminidase inhibitor of the new non-glycosyl of exploitation, and the relevant human body diseases for the treatment of has been opened up a new direction.
Table 1
Nd: inhibitor concentration suppresses active in 50% when 0.05mM.
Claims (14)
1. a naphthalimide derivative is characterized in that, described naphthalimide derivative is compound shown in the formula I, or it is at pharmacologically acceptable salts:
Among the formula I, R
1Be H, C
1～C
4Alkoxyl group,
Or halogen, wherein R
3And R
4Independently be selected from respectively C
1～C
4A kind of in the alkyl;
R
2Be H, hydroxyl or the amino C that replaces
1～C
4Alkyl, or group shown in the formula II:
Among the formula II, X is O, S, and NH, or
M is 0～6 integer; N is 0 or 1;
A is group shown in formula III or the formula IV:
Wherein, R
5～R
9Independently be selected from respectively: H, C
1～C
4Alkoxyl group, C
1～C
4A kind of in fluoroalkoxy, halogen, nitro or the formic acid carbalkoxy, or R
5～R
9Two of middle arbitrary neighborhoods be combined as the divalence phenyl or
All the other are H,
R
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C
1～C
4The phenyl or naphthyl that alkoxyl group replaces, all the other are
And R
10～R
13In have at least one to be
2. naphthalimide derivative as claimed in claim 1 is characterized in that, wherein R
1Be H, C
1～C
2Alkoxyl group, Cl, Br, I or
R wherein
3And R
4Independently be selected from respectively C
1～C
2A kind of in the alkyl.
3. naphthalimide derivative as claimed in claim 2 is characterized in that, wherein R
1Be H, CH
3O-, Br or-N (CH
3)
2
4. naphthalimide derivative as claimed in claim 1 is characterized in that, wherein R
2Be H, or hydroxyl or the amino C that replaces
1～C
2Alkyl.
5. such as claim 3 or 4 described naphthalimide derivatives, it is characterized in that, described naphthalimide derivative is:
2-(2-amino-ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-hydroxyethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-amino-ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-amino-ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-amino-ethyl)-6-dimethyl amido-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, or 2-(2-amino-ethyl)-6-bromo-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone.
6. naphthalimide derivative as claimed in claim 1 is characterized in that, wherein R
2Be group shown in the formula II, and A is group shown in the formula III; M is 0,1,2 or 3;
R wherein
5～R
9Independently be selected from respectively: H, C
1～C
2Alkoxyl group, C
1～C
2Fluoroalkoxy, halogen, nitro or-COOCH
3In a kind of,
Or
R
5～R
9Two of middle arbitrary neighborhoods be combined as the divalence phenyl or
All the other are H.
7. naphthalimide derivative as claimed in claim 6 is characterized in that, wherein R
5～R
9Independently be selected from respectively: H, methoxyl group, trifluoromethoxy, Cl ,-NO
2Or-COOCH
3In a kind of.
8. naphthalimide derivative as claimed in claim 7 is characterized in that, wherein R
2Be selected from: a kind of in the following groups:
9. such as claim 3 or 8 described naphthalimide derivatives, it is characterized in that, described naphthalimide derivative is: 2-(2-((2-(4-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(3-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(2-methoxyphenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(4-anisole sulfenyl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((3-(4-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((3-(3-methoxyphenoxy) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((3-(4-anisole sulfenyl) propyl group) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(benzo [d] [1,3] methylene-dioxy-5-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(3 for 2-for 2-, 4-dimethoxy phenoxy group) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(1 for 2-for 4-, 3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) oxyethyl group) methyl benzoate, 2-(2-((2-(4-chlorophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(4-nitrophenoxy) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-((4-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-((3-p-methoxy-phenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-((2 for 2-for 2-, the 4-Dimethoxyphenyl) amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((4-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((3-p-methoxy-phenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (2-((3 for 2-, the 4-Dimethoxyphenyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(1 for 2-for N-, 3-dioxy-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) ethyl) amino) ethyl)-the 4-methoxy benzamide, 2-(2-((2-(naphthalene-1-oxygen base) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, or 2-(2-((2-(naphthalene-1-is amino) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone.
10. naphthalimide derivative as claimed in claim 1 is characterized in that, wherein R
2Be group shown in the formula II, and A is group shown in the formula IV; M is 0,1,2 or 3;
R wherein
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, C
1～C
2The phenyl or naphthyl that alkoxyl group replaces, all the other are
And R
10～R
13In have at least one to be
11. naphthalimide derivative as claimed in claim 10 is characterized in that, wherein R
10～R
13Two of middle arbitrary neighborhoods or three 's the phenyl that is combined as divalence, the phenyl or naphthyl of methoxy substitution, all the other are
And R
10～R
13In have at least one to be
12. naphthalimide derivative as claimed in claim 11 is characterized in that, wherein R
2Be selected from: a kind of in the following groups:
13. such as claim 3 or 11 described naphthalimide derivatives, it is characterized in that, described naphthalimide derivative is: (((2-(1 for 2-for 2-, the 3-dioxoisoindolin) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(2-oxygen benzo [cd] indoles-1 (1H)-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, 2-(2-((2-(5-methoxyl group-2,3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(2 for 2-for 2-, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(2 for 2-for 2-, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-methoxyl group-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, (((2-(2 for 2-for 2-, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-dimethyl amine-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone, or 2-(((2-(2 for 2-, 3-dioxo indoline-1-yl) ethyl) amino) ethyl)-6-bromo-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-diketone.
14. such as naphthalimide derivative as described in any one in the claim 1～13 for the preparation of the application in the medicine of the treatment disease relevant with human beta-N-acetylhexosaminidase.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641825A (en) * | 2013-11-01 | 2014-03-19 | 大连理工大学 | Naphthalimide derivative and application thereof as enzyme inhibitor and pesticide |
| CN105777637A (en) * | 2014-12-22 | 2016-07-20 | 中国科学院化学研究所 | Water soluble mitochondrial targeting imaging probe and preparation method thereof |
| CN107383120A (en) * | 2017-07-31 | 2017-11-24 | 中国农业大学 | A kind of glycosyl naphthalimide derivative and preparation method and application |
| CN107513083A (en) * | 2017-09-07 | 2017-12-26 | 大连理工大学 | The preparation method of glycosyl naphthoyl imide compounds and application |
| CN112010838A (en) * | 2019-05-31 | 2020-12-01 | 中国科学院化学研究所 | Naphthalimide-indole derivative-based intracellular reticulum fluorescent probe and application thereof |
| CN114591239A (en) * | 2020-12-03 | 2022-06-07 | 中国科学院大连化学物理研究所 | Naphthalimide derivative and synthesis and application thereof |
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| WO2008106104A2 (en) * | 2007-02-26 | 2008-09-04 | Massachusetts Institute Of Technology | Environmentally sensitive fluorophores |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641825A (en) * | 2013-11-01 | 2014-03-19 | 大连理工大学 | Naphthalimide derivative and application thereof as enzyme inhibitor and pesticide |
| CN105777637A (en) * | 2014-12-22 | 2016-07-20 | 中国科学院化学研究所 | Water soluble mitochondrial targeting imaging probe and preparation method thereof |
| CN105777637B (en) * | 2014-12-22 | 2018-10-09 | 中国科学院化学研究所 | A kind of Mitochondrially targeted image probe of water solubility and preparation method thereof |
| CN107383120A (en) * | 2017-07-31 | 2017-11-24 | 中国农业大学 | A kind of glycosyl naphthalimide derivative and preparation method and application |
| CN107383120B (en) * | 2017-07-31 | 2019-08-20 | 中国农业大学 | A kind of glycosyl naphthalimide derivative and the preparation method and application thereof |
| CN107513083A (en) * | 2017-09-07 | 2017-12-26 | 大连理工大学 | The preparation method of glycosyl naphthoyl imide compounds and application |
| CN107513083B (en) * | 2017-09-07 | 2020-09-29 | 大连理工大学 | Preparation method and application of glycosyl naphthalimide compound |
| CN112010838A (en) * | 2019-05-31 | 2020-12-01 | 中国科学院化学研究所 | Naphthalimide-indole derivative-based intracellular reticulum fluorescent probe and application thereof |
| CN112010838B (en) * | 2019-05-31 | 2021-07-13 | 中国科学院化学研究所 | Naphthalimide-indole derivative-based intracellular reticulum fluorescent probe and application thereof |
| CN114591239A (en) * | 2020-12-03 | 2022-06-07 | 中国科学院大连化学物理研究所 | Naphthalimide derivative and synthesis and application thereof |
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