CN104761568A - Novel tetracyclonaphthooxazole derivative and preparation method thereof - Google Patents
Novel tetracyclonaphthooxazole derivative and preparation method thereof Download PDFInfo
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- CN104761568A CN104761568A CN201410002643.XA CN201410002643A CN104761568A CN 104761568 A CN104761568 A CN 104761568A CN 201410002643 A CN201410002643 A CN 201410002643A CN 104761568 A CN104761568 A CN 104761568A
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- MKSULDSEQKGEEL-UHFFFAOYSA-N CCCNC(C(c1c2cccc1)=O)=CC2=O Chemical compound CCCNC(C(c1c2cccc1)=O)=CC2=O MKSULDSEQKGEEL-UHFFFAOYSA-N 0.000 description 3
- GJQFBCILLJVRJX-UHFFFAOYSA-N CC(C)(C)OC(N(C)CCCNC(C(c1c2cccc1)=O)=CC2=O)=O Chemical compound CC(C)(C)OC(N(C)CCCNC(C(c1c2cccc1)=O)=CC2=O)=O GJQFBCILLJVRJX-UHFFFAOYSA-N 0.000 description 1
- ONDIEMRUFIBFKL-UHFFFAOYSA-N CC(C)(C)OC(N(C)CCc1nc(cc2OC(c3ccccc3)=C(c3ccccc3)c3cccc4c23)c4[o]1)=O Chemical compound CC(C)(C)OC(N(C)CCc1nc(cc2OC(c3ccccc3)=C(c3ccccc3)c3cccc4c23)c4[o]1)=O ONDIEMRUFIBFKL-UHFFFAOYSA-N 0.000 description 1
- PTENAJYNSNTREK-UHFFFAOYSA-N CC(c1nc(cc2OC(c3ccccc3)=C(c3ccccc3)c3cccc4c23)c4[o]1)OC(C)=O Chemical compound CC(c1nc(cc2OC(c3ccccc3)=C(c3ccccc3)c3cccc4c23)c4[o]1)OC(C)=O PTENAJYNSNTREK-UHFFFAOYSA-N 0.000 description 1
- VBRLZTLFLNZEPZ-UHFFFAOYSA-N CCCCC#Cc1ccccc1 Chemical compound CCCCC#Cc1ccccc1 VBRLZTLFLNZEPZ-UHFFFAOYSA-N 0.000 description 1
- 0 CCCCC(c1cccc2c11)=C(c3ccccc3)Oc1cc1c2[o]c(C(C)*)n1 Chemical compound CCCCC(c1cccc2c11)=C(c3ccccc3)Oc1cc1c2[o]c(C(C)*)n1 0.000 description 1
- HQIQGFVWCUDAGG-UHFFFAOYSA-N CCCCC(c1cccc2c11)=C(c3ccccc3)Oc1cc1c2[o]c(CC)n1 Chemical compound CCCCC(c1cccc2c11)=C(c3ccccc3)Oc1cc1c2[o]c(CC)n1 HQIQGFVWCUDAGG-UHFFFAOYSA-N 0.000 description 1
- MMGWBBCAKHJUPL-UHFFFAOYSA-N CCc(cc1)ccc1C#Cc1ccc(CC)cc1 Chemical compound CCc(cc1)ccc1C#Cc1ccc(CC)cc1 MMGWBBCAKHJUPL-UHFFFAOYSA-N 0.000 description 1
- CIHIDJAILQGNHD-UHFFFAOYSA-N CCc1nc(cc2OC(c3ccc(CC)cc3)=C(c3ccc(CC)cc3)c3cccc4c23)c4[o]1 Chemical compound CCc1nc(cc2OC(c3ccc(CC)cc3)=C(c3ccc(CC)cc3)c3cccc4c23)c4[o]1 CIHIDJAILQGNHD-UHFFFAOYSA-N 0.000 description 1
- RDBQALCVVRFKIC-UHFFFAOYSA-N CCc1nc2cc(OC(c3ccccc3)=C3c4ccccc4)c4c3cccc4c2[o]1 Chemical compound CCc1nc2cc(OC(c3ccccc3)=C3c4ccccc4)c4c3cccc4c2[o]1 RDBQALCVVRFKIC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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Abstract
The invention discloses a novel tetracyclonaphthooxazole derivative. The structure of the novel tetracyclonaphthooxazole derivative is represented by general formula (I) shown in the specification. The invention also discloses a preparation method of the tetracyclonaphthooxazole derivative. The method allows the tetracyclonaphthooxazole derivative to be innovatively synthesized through using a carbon hydrogen activation serial reaction with amino substituted quinone as a reaction substrate. The method has the advantages of simplicity, easy implementation and high efficiency. The synthetic tetracyclonaphthooxazole derivative has a similar structure with a traditional DNA clastogen, can inhibit cell proliferation and growth, and has antibacterial, antifungal, anti-HIV and antitumor bioactivity. The invention also discloses an application of above compounds as a cell proliferation and growth inhibitor, and an application of the compounds in the preparation of antitumor medicines.
Description
Technical field
The present invention relates to organic chemistry and medicinal chemistry art, be specifically related to a kind of novel tetracyclic Nai Bing oxazole analog derivative and preparation method thereof.
Background technology
Benzoxazole, Nai Bing oxazole are extensively present in various active natural product and synthetic molecules structure as advantage skeleton.There is antibacterium, antimycotic, AntiHIV1 RT activity, the multiple biological activity such as antitumor.
In recent years, scientist finds that again some contain the other biological active compound of benzoxazole, Nai Bing oxazole molecule of the skeleton successively.The people such as Gonz á lez in 1999 report that compound pseudopteroxazol can suppress tuberculosis bacteria to grow (Rodr í guez, A.D.; Ramire, C.; Rodr í guez, I.I.; Gonz á lez, E.Org.Lett.1999,1,527); The people such as Shin in 2013 report compound H erqueioxazole to aureus sortase A enzyme significant inhibit activities (Julianti, E.; Lee, J.; Liao, L.; Park, W.; Park, S.; Oh, D.; Oh, K.; Shin, J.Org.Lett.2013,15,1286).But existing naphthalene the synthetic method of oxazole analog derivative is comparatively loaded down with trivial details, combined coefficient is not high, limits the application of this compounds.
Summary of the invention
In order to solve the problems of the technologies described above, an object of the present invention is to provide a kind of novel tetracyclic Nai Bing oxazole analog derivative.This compounds can as DNA break reagent, can antiproliferative effect growth, has the potential biological activity such as antitumor, antibacterial.
Another object of the present invention is to provide the method for a kind of simple and easy to do, that combined coefficient is high preparation described Fourth Ring Nai Bing oxazole analog derivative, and the method is the method that the cascade reaction utilizing hydrocarbon activation to participate in carrys out novelty synthesis.
Another object of the present invention is also the application of above-claimed cpd as cell proliferation growth inhibitor, and is preparing the application in antitumor drug.
In order to realize above-mentioned order ground, the invention provides a kind of novel tetracyclic Nai Bing oxazole analog derivative, it has the structure shown in following general formula (I):
Wherein,
X is O or S.
Y is O or S.
Z is C or N.
R
1and R
2independently but be not side by side hydrogen, be separately halogen atom, hydroxyl, C
1-C
6alkoxyl group, amino, C
1-C
6alkylamino, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted phenyl; Or, R
1and R
2substituted or unsubstituted C can be connected to form
6-C
10aryl or five yuan or six membered heteroaryl, be preferably substituted or unsubstituted phenyl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, C
1-C
10alkyl, halo C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably halogen atom, carboxyl, C
1-C
6alkoxyl group, C
1-C
6alkyl or halo C
1-C
6alkyl.
R
3and R
4be separately hydrogen, halogen atom, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably H, C
1-C
6alkoxy carbonyl, C
1-C
6amido, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or C
1-C
6alkylamino; Or, R
3and R
4substituted or unsubstituted C can be connected to form
6-C
10aryl or five yuan or six membered heteroaryl, be preferably substituted or unsubstituted phenyl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or phenyl.
R
5and R
7be separately hydrogen, halogen atom, replacement or do not replace C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably H, replacement or do not replace C
1-C
6alkoxyl group, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, 3 to 6 yuan of oxa-s or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, be preferably halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or phenyl.
R
6for hydrogen, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted thiazolinyl, halo C
1-C
6alkyl, substituted or unsubstituted C
3-C
10cycloalkyl, substituted or unsubstituted C
3-C
6oxa-or azacycloalkyl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl carbonyl oxygen base, monosubstituted, two replacement or non-substituted-amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6oxa-or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, wherein, substituting group is selected from C
1-C
6alkyl, C
1-C
6carbonyl, C
1-C
6alkoxy carbonyl.
More preferably, in general formula (I):
X is O.
Y is O.
Z is N.
R
1and R
2be separately substituted or unsubstituted C
1-C
6alkyl or phenyl, C
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylamino.
R
3and R
4be separately H, halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, C
1-C
6alkoxyl group or C
1-C
6alkylamino; Or, R
3and R
4naphthalene nucleus can be connected to form.
R
5and R
7be separately H, halogen atom, C
1-C
6alkoxy carbonyl, substituted or unsubstituted C
1-C
6alkyl or phenyl, replacement or do not replace C
1-C
6alkoxyl group or C
1-C
6alkylamino; Wherein, substituting group is selected from halogen atom, hydroxyl, amino, C
6-C
10aryl or five yuan or six membered heteroaryl.
R
6for hydrogen, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted thiazolinyl; Substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl carbonyl oxygen base, monosubstituted, two replacement or non-substituted-amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6oxa-or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from C
1-C
6alkyl, C
1-C
6carbonyl, C
1-C
6alkoxy carbonyl.
In the present invention, make as given a definition:
Described halogen atom refers to F, Cl, Br or I.
Described C
1-C
10alkyl refers to straight or branched alkyl main chain with 1 to 10 carbon atom, term " C
1-C
6alkyl " there is similar implication.Such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, base etc.
Described C
1-C
10alkoxyl group refers to straight or branched alkoxyl group main chain with 1 to 10 carbon atom, term " C
1-C
6alkoxyl group " there is similar implication.Such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy etc.
Described halo C
1-C
10alkyl refers to the C replaced with one or more halogen atom
1-C
10alkyl, term " halo C
1-C
6alkyl " there is similar implication.Such as trifluoromethyl etc.
Described C
3-C
10cycloalkyl refers to the fatty carbocylic radical with 3 to 10 carbon atoms, comprises monocycle and ring, bridged ring, volution etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl etc.
Described C
1-C
6alkoxy carbonyl refers to the alkoxy carbonyl with 1 to 6 carbon atom, such as methoxycarbonyl, ethoxy carbonyl etc.
Described C
1-C
6alkyl carbonyl oxygen base refers to the alkyl carbonyl oxygen base with 1 to 6 carbon atom, such as acetoxyl group etc.
Described C
1-C
6amido refers to the carbonylamino with 1 to 6 carbon atom, such as kharophen, propionamido, butyrylamino etc.
Described C
6-C
10aryl refers to aromaticity carbocylic radical ring with 6 to 10 carbon atoms, such as, and phenyl, naphthyl etc.
Described five yuan or six membered heteroaryl refer to be had at least one and is selected from heteroatomic five yuan or hexa-atomic aromaticity cyclic groups in N, O and S, such as thiophene cyclic group, thiazole cyclic group, pyrazoles cyclic group, imidazoles cyclic group, pyridine cyclic group, pyrazine cyclic group, pyrimidine cyclic group etc. on ring.
Described C
3-C
6cycloaliphatic ring refers to the fatty carbocyclic ring with 3 to 6 carbon atoms, such as cyclopropane, tetramethylene, pentamethylene, hexanaphthene.
Described C
3-C
6oxa-or azepine cycloaliphatic ring alkyl refer to be had at least one and is selected from the heteroatomic cycloaliphatic ring containing 3 to 6 atoms in N, O and S, such as Pyrrolidine, morpholine, piperazine, piperidines etc. on ring.
Most preferably, the compound shown in general formula of the present invention (I) is selected from following compounds:
The invention provides the preparation method of compound shown in general formula (I), it is synthesized by following route:
2-substituted-amino quinones is activated by C-H the cascade reaction participated in replacement alkynes and forms target compound (I), reaction formula is as follows:
Here activate 5 of quinone with metal catalyst Rh, add oxygenant Cu (OAc)
2.H
2o, additive A gSbF
6, Reactive Synthesis in solvent t-AmOH.
The present invention also provides above-mentioned novel tetracyclic Nai Bing oxazole analog derivative as the application of cytostatic agent, and is preparing the application in antitumor drug.
The present invention takes polysubstituted method, utilize the amino quinone that replaces as the substrate reacted, that uses the method innovation of the cascade reaction of hydrocarbon activation participation has synthesized some Fourth Ring Nai Bing oxazole analog derivative skeletons being in the past difficult to build, simple synthetic method is easy, efficiency is high, significant for the hydrocarbon priming reaction of more deep understanding, cascade reaction.The product of the inventive method gained has no bibliographical information, belong to new compound, Fourth Ring Nai Bing oxazole analog derivative and traditional DNA break agent similar of synthesis, can grow by antiproliferative effect, has antibacterium, antimycotic, AntiHIV1 RT activity, the biological activity such as antitumor.
Embodiment
Following examples are intended to set forth instead of limit the scope of the invention.
Except as otherwise noted, the preparation adopted in the present invention and testing method and equipment etc. are method and apparatus conventional in this area.Agents useful for same is analytical pure or chemical pure.
Embodiment 1.
The preparation of 2-substituted-amino quinones substrate is with reference to Khodade, V.S.; Dharmaraja, A.T.; Chakrapani, H.Bioorg.Med.Chem.Lett.2012,22,3766.
Take 86mg (0.4mmol) 2-n-propylamine base-1,4-naphthoquinone, 107mg (0.6mmol) dibenzenyl, 12mg (0.02mmol) [Rh (Cp*) Cl
2]
2(Cp*=pentamethylcyclopentadiene), 12mg (0.04mmol) AgSbF
6with 160mg (0.8mmol) Cu (OAc)
2.H
2o adds in round bottom reaction flask, dissolves, heat 6h and reacted at 120 DEG C with 2mL t-AmOH.Add 10mL water, be extracted with ethyl acetate three times (5mL x3), merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, silica gel column chromatography is separated and obtains 113mg light yellow solid Compound 1, yield 73%; 25mg light yellow solid Compound 29, yield 14%.
Compound 1:
1h NMR (300MHz, CDCl
3) δ 7.60 (d, J=8.4Hz, 1H), 7.33 (m, 5H), 7.20 (m, 7H), 6.49 (d, J=7.4Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 1.50 (t, J=7.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 168.2,150.0 (2), 140.7,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.7,128.6,127.7,127.6,120.6,120.1,116.3,116.1,115.8,98.5,22.4,11.1; EI-MS (m/z) 389 (M
+); HRMS C
27h
19nO
2[M
+], calculated value: 389.1416, measured value: 389.1418.
Compound 29:
1H NMR (300MHz, CDCl3) δ 7.65 (d, J=8.3Hz, 1H), 7.35 (m, 5H), 7.23 (m, 7H), 6.55 (d, J=7.5Hz, 1H), 6.18 (q, J=6.7Hz, 1H), 2.19 (s, 3H), 1.80 (d, J=6.7Hz, 3H); 13C NMR (126MHz, CDCl3) δ 170.0,164.0,150.4,150.1,140.9,138.2,135.2,133.9,133.2,131.1,129.2129.0,128.9,128.6,127.7 (2), 121.2,120.3,116.4,116.3,98.7,65.4,21.0,18.6; EI-MS (m/z) 447 (M+); HRMSC29H21NO4 [M+], calculated value: 447.1471, measured value: 447.1473.
Embodiment 2.
Except dibenzenyl, 110mg light yellow solid Compound 2 is prepared according to the method for embodiment 1, yield 66% except replacing with two p-methylphenyl acetylene.27mg light yellow solid Compound 30, yield 14%.
Compound 2:
1h NMR (400MHz, CDCl
3) δ 7.62 (d, J=8.3Hz, 1H), 7.27 (m, 5H), 7.17 (m, 3H), 7.03 (d, J=8.1Hz, 2H), 6.53 (m, 1H), (3.06 q, J=7.6Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H), (1.53 t, J=7.6Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 168.1,150.0,149.9,140.5,138.5,138.4,137.1,133.5,132.3,131.2,130.9,129.8,128.8,128.6,128.4,120.5,120.0,115.8,115.6,98.3,22.3,21.3 (2), 11.1; EI-MS (m/z) 417 (M
+), HRMS C
29h
23nO
2[M
+], calculated value: 417.1729, measured value: 417.1728.
Compound 30:
1h NMR (300MHz, CDCl
3) δ 7.63 (dd, J=8.3,0.9Hz, 1H), 7.29 (dd, J=8.2,7.5Hz, 1H), 7.16 (m, 7H), 7.00 (d, J=7.9Hz, 2H), 6.54 (dd, J=7.4,0.9Hz, 1H), 6.18 (q, J=6.7Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 1.80 (d, J=6.7Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 170.0,163.9,150.4150.0,140.8,138.5,138.1,137.2,133.5,132.2,131.1,130.8,129.9,128.9,128.8,128.4,121.1,120.2,116.2,116.1,115.6,98.4,65.4,21.3 (2), 21.0,18.6; EI-MS (m/z) 475 (M
+), HRMS C
31h
25nO
4[M
+], calculated value: 475.1784, measured value: 475.1778.
Embodiment 3.
Except dibenzenyl, 117mg light yellow solid Compound 3 is prepared according to the method for embodiment 1, yield 64% except replacing with two rubigan acetylene.
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.4Hz, 1H), 7.36 (d, J=8.3Hz, 2H), 7.24 (m, 2H), 7.18 (m, 4H), 7.14 (m, 2H), (6.43 d, J=7.4Hz, 1H), (3.02 q, J=7.6Hz, 2H), (1.49 t, J=7.6Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 168.3,149.5,149.1,140.7,138.6,134.7,133.8,133.5,132.4,132.1,130.2,129.6,128.6,128.1,120.3,120.0,116.6,115.7,115.5,98.7,22.3,11.1; EI-MS (m/z) 457 (M
+), HRMS C
27h
17nO
2cl
2[M
+], calculated value: 457.0636, measured value: 457.0633.
Embodiment 4.
Except dibenzenyl, 102mg light yellow solid Compound 4 is prepared according to the method for embodiment 1, yield 60% except replacing with two pairs of fluorophenylacetylene; 25mg light yellow solid Compound 31, yield 13%.
Compound 4:
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.1Hz, 1H), 7.27 (m, 3H), (7.18 d, J=5.5Hz, 2H), 7.14 (s, 1H), 7.08 (t, J=8.2Hz, 2H), (6.88 t, J=8.5Hz, 2H), 6.45 (d, J=7.2Hz, 1H), 3.02 (q, J=7.5Hz, 2H), 1.49 (t, J=7.5Hz, 3H);
13cNMR (126MHz, CDCl
3) δ 167.8,163.0,162.7,161.1,160.8,149.2,148.9,140.2,138.2,132.4,132.3 (2), 130.5 (3), 130.4,129.5 (2), 128.2,119.9,119.6,116.0,115.9,115.8,115.1,114.8,114.5,114.3,98.2,21.9,10.6; EI-MS (m/z) 425 (M
+), HRMS C
27h
17nF
2o
2[M
+], calculated value: 425.1227, measured value: 425.1226.
Compound 31:
1h NMR (300MHz, CDCl
3) δ 7.66 (d, J=8.4Hz, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.20 (m, 3H), 7.08 (t, J=8.6Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 6.50 (d, J=7.4Hz, 1H), (6.17 q, J=6.7Hz, 1H), 2.18 (s, 3H), 1.80 (d, J=6.8Hz, 3H);
13cNMR (101MHz, CDCl
3) δ 170.0,164.1,163.8,163.5,161.3,161.0,150.0,149.4,140.9,138.1,132.8,132.7,131.0,130.9,129.8,128.9,120.9,120.2,116.6,116.5,116.3,116.2,115.2,115.0,114.8,98.8,65.4,21.0,18.6; EI-MS (m/z) 483 (M
+), HRMS C
29h
19nF
2o
4[M
+], calculated value: 483.1282, measured value: 483.1278.
Embodiment 5.
Except dibenzenyl, 109mg light yellow solid Compound 5 is prepared according to the method for embodiment 1, yield 61% except replacing with two pairs of ethylphenyl acetylene.
1h NMR (300MHz, CDCl
3) δ 7.58 (d, J=7.8Hz, 1H), 7.25 (m, 4H), 7.19 (s, 1H), 7.15 (d, J=5.9Hz, 3H), 7.01 (d, J=8.2Hz, 2H), 6.50 (d, J=7.0Hz, 1H), (3.02 q, J=7.6Hz, 2H), (2.68 q, J=7.6Hz, 2H), (2.57 q, J=7.6Hz, 2H), (1.49 t, J=7.6Hz, 3H), (1.28 t, J=7.6Hz, 3H), (1.17 t, J=7.6Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 168.1,150.0,149.9,144.7,143.5,138.5,133.6,132.5,131.4,130.9,128.8,128.7,128.6,127.2,120.5,120.1,115.8,115.7,98.3,28.6 (2), 22.3,15.4,15.2,11.1; EI-MS (m/z) 445 (M
+), HRMS C
31h
27nO
2[M
+], calculated value: 445.2042, measured value: 445.2040.
Embodiment 6.
Except dibenzenyl, 86mg light yellow solid Compound 6 is prepared according to the method for embodiment 1, yield 48% except replacing with di-p-methoxy phenylacetylene.
1h NMR (300MHz, CDCl
3) δ 7.57 (d, J=8.3Hz, 1H), 7.25 (m, 3H), 7.15 (d, J=9.0Hz, 3H), 6.92 (d, J=8.6Hz, 2H), 6.71 (d, J=8.8Hz, 2H), 6.49 (d, J=7.4Hz, 1H), 3.82 (s, 3H), (3.75 s, 3H), 3.02 (q, J=7.6Hz, 2H), 1.49 (t, J=7.6Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 168.1,159.5,158.8,150.0,149.8,140.5,138.5,133.7,132.2,130.3,128.7,127.6,126.5,120.4,120.0,115.7,115.4,114.7,114.6,113.1,98.2,55.2 (2), 22.3,11.1; EI-MS (m/z) 449 (M
+), HRMS C
29h
23nO
4[M
+], calculated value: 449.1627, measured value: 449.1631.
Embodiment 7.
Except dibenzenyl, 149mg light yellow solid Compound 7 is prepared according to the method for embodiment 1, yield 71% except replacing with two p-trifluoromethyl phenyl acetylene.
1h NMR (400MHz, CDCl
3) δ 7.70 (d, J=8.1Hz, 3H), 7.50 (d, J=8.3Hz, 2H), 7.42 (d, J=8.2Hz, 4H), 7.32 (t, J=7.9Hz, 1H), 7.21 (s, 1H), 6.45 (d, J=7.3Hz, 1H), 3.07 (
q, J=7.6Hz, 2H), 1.54 (t, J=7.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 168.5,149.4,149.0,140.8,138.7,137.0,132.0,131.5,130.8,130.5,130.4130.1,129.2,128.6,126.4,126.3,124.9 (2), 122.9,122.6,120.4,120.1,117.1,116.4,116.0,99.1,22.3,11.1; EI-MS (m/z) 525 (M
+), HRMSC
29h
17nF
6o
2[M
+], calculated value: 525.1163, measured value: 525.1159.
Embodiment 8.
Except dibenzenyl, 83mg light yellow solid Compound 8 is prepared according to the method for embodiment 1, yield 52% except replacing with dithienyl acetylene.
1h NMR (300MHz, CDCl
3) δ 7.59 (t, J=5.6Hz, 2H), 7.26 (m, 3H), 7.19 (s, 2H), 7.07 (d, J=2.6Hz, 1H), 6.94 (m, 1H), (6.48 d, J=7.3Hz, 1H), (3.02 q, J=7.6Hz, 2H), (1.49 t, J=7.6Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 168.2,149.1,146.8,140.8,138.5,135.6,135.2,133.5,129.9,128.8,128.7,128.4,128.3,128.2,126.7,119.8,119.7,116.2,116.1,107.2,98.8,22.3,11.1; EI-MS (m/z) 401 (M
+), HRMS C
23h
15nO
2s
2[M
+], calculated value: 401.0544, measured value: 401.0536.
Embodiment 9.
Except dibenzenyl, 86mg light yellow solid Compound 9 is prepared according to the method for embodiment 1, yield 67% except replacing with diη-propyl acetylene; 44mg light yellow solid Compound 32, yield 29%.
Compound 9:
1h NMR (300MHz, CDCl
3) δ 7.55 (d, J=8.3Hz, 1H), 7.36 (m, 1H), 6.99 (s, 1H), 6.79 (d, J=7.3Hz, 1H), (2.99 q, J=7.6Hz, 2H), 2.40 (m, 4H), 1.70 (m, 2H), 1.56 (m, 2H), 1.46 (t, J=7.6Hz, 3H), 1.01 (td, J=7.3,1.5Hz, 6H);
13cNMR (126MHz, CDCl
3) δ 167.9,152.9,150.0,140.3,138.3,132.1,128.7,120.8,120.2,114.9,112.6,110.6,97.7,32.7,28.4,22.3,21.3,21.1,14.3,13.9,11.1; EI-MS (m/z) 321 (M
+), HRMS C
21h
23nO
2[M
+], calculated value: 321.1729, measured value: 321.1727.
Compound 32:
1h NMR (300MHz, CDCl
3) δ 7.60 (d, J=8.3Hz, 1H), 7.40 (t, J=7.9Hz, 1H), 7.02 (s, 1H), 6.84 (d, J=7.4Hz, 1H), 6.15 (q, J=6.7Hz, 1H), 2.40 (m, 4H), 2.17 (s, 3H), 1.78 (d, J=6.7Hz, 3H), 1.71 (m, 2H), 1.56 (m, 2H), 1.01 (t, J=7.3Hz, 6H);
13c NMR (126MHz, CDCl
3) δ 170.0,163.7,153.0,150.4,140.5,137.9,132.1,128.9,121.3,120.4,115.2,113.2,110.6,97.8,65.4,32.6,28.4,21.2,21.0 (2), 18.6,14.3,13.9; EI-MS (m/z) 379 (M
+), HRMS C
23h
25nO
2[M
+], calculated value: 379.1784, measured value: 379.1791.
Embodiment 10.
Except dibenzenyl, 93mg light yellow solid Compound 10 is prepared according to the method for embodiment 1, yield 63% except replacing with phenyl n-butyl-acetylene; 46mg light yellow solid Compound 33, yield 27%.
Compound 10:
1h NMR (300MHz, CDCl
3) δ 7.64 (d, J=8.3Hz, 1H), 7.55 (m, 2H), 7.44 (m, 4H), 7.06 (s, 1H), 6.93 (d, J=7.3Hz, 1H), 3.01 (q, J=7.6Hz, 2H), 2.42 (m, 2H), 1.59 (m, 2H), (1.48 t, J=7.6Hz, 3H), 1.33 (m, 2H), 0.86 (t, J=7.3Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 168.1,150.6,150.0,140.5,138.5,134.8,131.8,129.0,128.9,128.7,128.3,120.9,120.2,115.9,113.7,112.8,98.2,30.3,26.8,22.8,22.3,13.8,11.1; EI-MS (m/z) 369 (M
+), HRMS C
25h
23nO
2[M
+], calculated value: 369.1729, measured value: 369.1723.
Compound 33:
1h NMR (300MHz, CDCl
3) δ 7.69 (d, J=8.3Hz, 1H), 7.56 (m, 2H), 7.46 (m, 4H), 7.08 (s, 1H), 6.98 (d, J=7.4Hz, 1H), 6.17 (q, J=6.7Hz, 1H), 2.43 (m, 2H), 2.18 (s, 3H), 1.79 (d, J=6.7Hz, 3H), 1.58 (m, 2H), 1.33 (m, 2H), 0.86 (t, J=7.3Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 170.0,163.9,150.6,150.4,140.7,138.0,134.6,131.8,129.1,128.9,128.4,121.5,120.3,116.1,114.3,112.8,98.3,65.4,30.3,26.8,22.8,21.1,18.6,13.8; EI-MS (m/z) 427 (M
+), HRMSC
27h
25nO
4[M
+], calculated value: 427.1784, measured value: 427.1767.
Embodiment 11 and 12.
Except dibenzenyl, 45mg light yellow solid Compound 11 (yield 38%) and 43mg light yellow solid Compound 12 (yield 37%) is prepared according to the method for embodiment 1 except replacing with methyl n-propyl acetylene.
Compound 11:
1h NMR (300MHz, CDCl
3) δ 7.57 (dd, J=8.3,0.7Hz, 1H), 7.39 (m, 1H), 7.02 (s, 1H), 6.75 (d, J=6.6Hz, 1H), 3.00 (q, J=7.6Hz, 2H), 2.44 (m, 2H), 1.94 (s, 3H), (1.72 m, 2H), 1.47 (t, J=7.6Hz, 3H), 1.00 (t, J=7.4Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 167.9,152.5,150.0,140.3,138.4,133.0,128.8,120.3,119.9,115.1,112.5,106.1,97.8,32.9,22.4,21.1,13.8,12.3,11.2; EI-MS (m/z) 293 (M
+), HRMS C
19h
19nO
2[M
+], calculated value: 293.1416, measured value: 293.1416.
Compound 12:
1h NMR (400MHz, CDCl
3) δ 7.58 (d, J=8.2Hz, 1H), 7.40 (m, 1H), (7.03 s, 1H), 6.81 (d, J=7.3Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 2.41 (m, 2H), 2.16 (s, 3H), (1.60 m, 2H), 1.51 (t, J=7.6Hz, 3H), 1.04 (t, J=7.4Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 167.9,149.9,149.4,140.4,138.3,132.0,128.7,120.8,120.2,114.9,112.3,110.6,97.8,28.6,22.3,20.8,17.1,14.2,11.1; EI-MS (m/z) 293 (M
+), HRMS C
19h
19nO
2[M
+], calculated value: 293.1416, measured value: 293.1415.
Embodiment 13.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 97mg light yellow solid Compound 13 according to the method for embodiment 1, yield 60% with 2-n-butyl amine base-Isosorbide-5-Nitrae naphthoquinones; 50mg light yellow solid Compound 34, yield 27%.
Compound 13:
1h NMR (300MHz, CDCl
3) δ 7.60 (d, J=8.4Hz, 1H), 7.32 (m, 5H), 7.23 (m, 6H), 7.18 (s, 1H), 6.49 (d, J=7.4Hz, 1H), 2.97 (t, J=7.5Hz, 2H), 1.98 (m, 2H), (1.08 t, J=7.4Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 167.2,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.7,128.6,127.7,127.6,120.6,120.1,116.3,116.2,115.8,98.5,30.7,20.5,13.9; EI-MS (m/z) 403 (M
+), HRMS C
28h
21nO
2[M
+], calculated value: 403.1572, measured value: 403.1563.
Compound 34:
1h NMR (300MHz, CDCl
3) δ 7.65 (dd, J=8.4,0.9Hz, 1H), 7.32 (m, 6H), 7.22 (m, 6H), 6.54 (dd, J=7.4,0.9Hz, 1H), 6.00 (t, J=6.8Hz, 1H), 2.18 (m, 5H), (1.05 t, J=7.4Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 170.2,163.5,150.3,150.1,140.8,138.2,135.2,133.9,133.2,131.1,129.2,129.0,128.9,128.6,127.7 (2), 121.1,120.3,116.4 (2), 116.3,98.7,70.2,26.3,20.9,9.5; EI-MS (m/z) 461 (M
+), HRMS C
30h
23nO
4[M
+], calculated value: 461.1627, measured value: 461.1622.
Embodiment 14.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 105mg light yellow solid Compound 14 according to the method for embodiment 1, yield 63% with 2-pentylamine base-Isosorbide-5-Nitrae naphthoquinones; 40mg light yellow solid Compound 35, yield 21%.
Compound 14:
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.3Hz, 1H), 7.28 (m, 12H), 6.49 (d, J=7.4Hz, 1H), 2.99 (t, J=7.6Hz, 2H), 1.92 (m, 2H), 1.49 (m, 2H), 0.99 (t, J=7.3Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 167.4,150.0,149.9,140.6,138.6,135.3,134.0,133.1,131.1,129.1,128.9,128.6,128.5,127.7,127.6,120.5,120.1,116.2,116.1,115.7,98.5,29.1,28.5,22.3,13.7; EI-MS (m/z) 417 (M
+), HRMSC
29h
23nO
2[M
+], calculated value: 417.1729, measured value: 417.1735.
Compound 35:
1h NMR (400MHz, CDCl
3) δ 7.69 (d, J=8.3Hz, 1H), 7.37 (m, 6H), 7.25 (m, 6H), 6.58 (d, J=7.4Hz, 1H), 6.11 (t, J=6.9Hz, 1H), 2.23 (s, 3H), 2.17 (m, 2H), 1.51 (m, 2H), (1.03 t, J=7.4Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 170.2,163.7,150.3,150.0,140.7,138.1,135.1,133.9,133.1,131.1,129.1,129.0,128.8,128.6,127.7 (2), 121.0,120.2,116.4,116.3,116.2,98.7,68.8,35.0,20.9,18.4,13.6; EI-MS (m/z) 475 (M
+), HRMS C
31h
25nO
4[M
+], calculated value: 475.1784, measured value: 475.1784.
Embodiment 15.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 90mg light yellow solid Compound 15 according to the method for embodiment 1, yield 54% with 2-isoamylamino-Isosorbide-5-Nitrae naphthoquinones; 30mg light yellow solid Compound 36, yield 16%.
Compound 15:
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.4Hz, 1H), 7.33 (m, 5H), 7.25 (m, 3H), 7.18 (m, 4H), 6.50 (d, J=7.4Hz, 1H), 2.87 (d, J=7.2Hz, 2H), 2.35 (m, 1H), (1.07 d, J=6.7Hz, 6H);
13c NMR (126MHz, CDCl
3) δ 166.7,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.6,128.5,127.7,127.6,120.6,120.1,116.2 (2), 115.7,98.5,37.7,27.7,22.5; EI-MS (m/z) 417 (M
+), HRMS C
29h
23nO
2[M
+], calculated value: 417.1729, measured value: 417.1721.
Compound 36:
1h NMR (400MHz, CDCl
3) δ 7.67 (d, J=8.3Hz, 1H), 7.34 (m, 6H), 7.23 (m, 6H), 6.56 (d, J=7.3Hz, 1H), 5.84 (d, J=6.8Hz, 1H), 2.52 (m, 1H), 2.23 (s, 3H), 1.10 (d, J=6.8Hz, 3H), (1.04 d, J=6.8Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 170.3,163.3,150.3,150.0,140.6,138.2,135.2,133.9,133.1,131.1,129.1,129.0,128.8,128.6,127.7,127.6,121.0,120.2,116.4,116.3,116.2,98.7,73.7,31.9,20.8,18.3,18.0; EI-MS (m/z) 475 (M
+), HRMS C
31h
25nO
4[M
+], calculated value: 475.1784, measured value: 475.1790.
Embodiment 16.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 116mg light yellow solid Compound 16 according to the method for embodiment 1, yield 67% with the just own amino of 2--Isosorbide-5-Nitrae naphthoquinones; 33mg light yellow solid Compound 37, yield 17%.
Compound 16:
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.3Hz, 1H), 7.26 (m, 12H), 6.49 (d, J=7.3Hz, 1H), 2.98 (t, J=7.7Hz, 2H), 1.94 (m, 2H), (1.42 d, J=3.2Hz, 4H), 0.93 (t, J=6.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 167.4,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.6,128.5,127.7,127.6,120.5,120.1,116.2,116.1,115.7,98.5,31.4,28.8,26.7,22.3,13.9; EI-MS (m/z) 431 (M
+), HRMS C
30h
25nO
2[M
+], calculated value: 431.1885, measured value: 431.1894.
Compound 37:
1h NMR (300MHz, CDCl
3) δ 7.65 (d, J=8.1Hz, 1H), 7.28 (m, 12H), 6.54 (d, J=7.1Hz, 1H), (6.05 t, J=6.9Hz, 1H), 2.19 (s, 3H), 2.15 (m, 2H), 1.39 (m, 4H), 0.91 (t, J=6.9Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 170.2,163.7,150.3,150.0,140.7,138.2,135.2,133.9,133.2,131.1,129.1,129.0,128.8,128.6,127.7 (2), 121.1,120.3,116.4,116.3,116.2,98.7,69.0,32.7,27.1,22.3,20.9,13.9; EI-MS (m/z) 489 (M
+), HRMS C
32h
27nO
4[M
+], calculated value: 489.1940, measured value: 489.1948.
Embodiment 17.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 141mg light yellow solid Compound 17 according to the method for embodiment 1 with 2-(3-phenyl) the third amino-Isosorbide-5-Nitrae naphthoquinones.Yield 76%.
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=8.3Hz, 1H), 7.28 (m, 17H), 6.51 (d, J=7.3Hz, 1H), 3.29 (m, 4H);
13c NMR (101MHz, CDCl
3) δ 166.3,150.0,140.6,140.2,138.5,135.2,134.0,133.2,131.1,129.1,128.9,128.7,128.6,128.5,128.3,127.7,127.6,126.5,120.6,120.1,116.2,116.1,115.8,98.5,33.1,30.7; EI-MS (m/z) 465 (M
+), HRMS C
33h
23nO
2[M
+], calculated value: 465.1729, measured value: 465.1728.
Embodiment 18.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 153mg light yellow solid Compound 18 according to the method for embodiment 1, yield 95% with 2-i-butylamino-Isosorbide-5-Nitrae naphthoquinones.
1h NMR (400MHz, CDCl
3) δ 7.66 (d, J=8.3Hz, 1H), 7.40 (m, 3H), 7.34 (m, 2H), 7.29 (m, 3H), 7.23 (m, 4H), (6.54 d, J=7.3Hz, 1H), (3.35 hept, J=7.0Hz, 1H), (1.55 d, J=7.0Hz, 6H);
13c NMR (126MHz, CDCl
3) δ 171.4,150.0,149.9,140.6,138.5,135.3,134.1,133.2,131.1,129.1,129.0,128.6 (2), 127.7,127.6,120.6,120.2,116.3,116.2,115.8,98.6,29.1,20.6; EI-MS (m/z) 403 (M
+), HRMS C
28h
21nO
2[M
+], calculated value: 403.1572, measured value: 403.1566.
Embodiment 19.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 123mg light yellow solid Compound 19 according to the method for embodiment 1, yield 74% with new penta amino of 2--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (400MHz, CDCl
3) δ 7.67 (d, J=8.2Hz, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 7.29 (m, 3H), 7.22 (m, 4H), 6.54 (d, J=7.3Hz, 1H), 1.58 (s, 9H);
13cNMR (126MHz, CDCl
3) δ 173.6,150.0,149.9,140.6,138.5,135.4,134.1,133.2,131.2,129.1,129.0,128.6 (2), 127.7,127.6,120.6,120.2,116.3,116.2,115.7,98.7,34.4,28.7; EI-MS (m/z) 417 (M
+), HRMS C
29h
23nO
2[M
+], calculated value: 417.1729, measured value: 417.1728.
Embodiment 20.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 149mg light yellow solid Compound 20 according to the method for embodiment 1, yield 93% with 2-cyclopropyl methylamino--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (400MHz, CDCl
3) δ 7.60 (d, J=8.3Hz, 1H), 7.39 (m, 3H), 7.34 (m, 2H), 7.28 (m, 3H), 7.21 (m, 3H), 7.14 (s, 1H), 6.51 (d, J=7.3Hz, 1H), 2.30 (m, 1H), 1.35 (m, 2H), 1.23 (m, 2H);
13c NMR (126MHz, CDCl
3) δ 168.6,150.0,140.2,138.9,135.3,134.1,133.2,131.1,129.1,129.0,128.6,128.5,127.7,127.6,120.3,119.9,116.3,116.0,115.5,98.3,9.6,9.3; EI-MS (m/z) 401 (M
+), HRMSC
28h
19nO
2[M
+], calculated value: 401.1416, measured value: 401.1414.
Embodiment 21.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 127mg light yellow solid Compound 21 according to the method for embodiment 1, yield 64% with 2-adamantyl methylamino--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (400MHz, CDCl
3) δ 7.66 (d, J=8.3Hz, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 7.29 (m, 3H), 7.22 (m, 4H), 6.52 (d, J=7.3Hz, 1H), 2.26 (d, J=2.7Hz, 6H), 2.19 (s, 3H), (1.88 t, J=2.8Hz, 6H);
13c NMR (101MHz, CDCl
3) δ 173.1,150.0,149.8,140.3,138.4,135.3,134.0,133.1,131.1,129.1,129.0,128.5,127.7,127.6,120.5,120.1,116.2,115.6,98.6,40.4,36.5,36.3,28.0; EI-MS (m/z) 495 (M
+), HRMS C
35h
29nO
2[M
+], calculated value: 495.2198, measured value: 495.2197.
Embodiment 22.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 93mg light yellow solid Compound 22 according to the method for embodiment 1, yield 45% with 2-N-Boc-N-methyl-prop diamino methylamino--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (400MHz, CDCl
3) δ 7.65 (d, J=8.3Hz, 1H), 7.39 (m, 3H), 7.34 (m, 2H), 7.29 (m, 3H), 7.23 (m, 3H), 7.19 (s, 1H), 6.55 (d, J=7.4Hz, 1H), 3.81 (t, J=6.8Hz, 2H), (3.24 s, 2H), 2.93 (d, J=20.9Hz, 3H), 1.43 (d, J=25.7Hz, 9H);
13c NMR (126MHz, CDCl
3) δ 164.6,155.4,150.1,150.0,140.8,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.8,128.6,127.7 (2), 120.7,120.2,116.3,116.2,116.0,98.5,79.8,47.0,34.4,29.7,28.4; EI-MS (m/z) 518 (M
+), HRMS C
33h
30n
2o
4[M
+], calculated value: 518.2206, measured value: 518.2205.
Embodiment 23.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 151mg light yellow solid Compound 23 according to the method for embodiment 1, yield 82% with 2-(2-THP trtrahydropyranyl) ethylamino-Isosorbide-5-Nitrae naphthoquinones; 29mg light yellow solid Compound 38, yield 14%.
Compound 23:
1h NMR (300MHz, CDCl
3) δ 7.61 (d, J=7.7Hz, 1H), 7.36 (m, 3H), 7.30 (m, 3H), 7.22 (m, 5H), 7.15 (s, 1H), 6.51 (d, J=6.9Hz, 1H), 3.98 (dd, J=11.4,3.0Hz, 2H), 3.44 (td, J=11.7,1.6Hz, 2H), 2.94 (d, J=7.1Hz, 2H), 2.25 (m, 1H), 1.74 (d, J=11.3Hz, 2H), 1.50 (ddd, J=25.2,12.3,4.4Hz, 2H);
13c NMR (126MHz, CDCl
3) δ 167.0,151.5,142.1,140.0,136.7,135.4,134.6,132.5,130.6,130.4,130.2,130.0,129.2,129.1,122.1,121.5,117.7,117.6,117.3,99.9,69.2,37.4,35.5,34.3; EI-MS (m/z) 459 (M
+), HRMS C
31h
25nO
3[M
+], calculated value: 459.1834, measured value: 459.1833.
Compound 38:
1h NMR (300MHz, CDCl
3) δ 7.65 (dd, J=8.3,0.8Hz, 1H), 7.28 (m, 12H), 6.55 (dd, J=7.4,0.7Hz, 1H), 5.88 (d, J=7.2Hz, 1H), 4.00 (t, J=11.1Hz, 2H), 3.42 (t, J=11.7Hz, 2H), 2.45 (m, 1H), 2.20 (s, 3H), 1.77 (d, J=12.0Hz, 1H), 1.60 (m, 2H), 1.50 (d, J=11.4Hz, 1H);
13c NMR (126MHz, CDCl
3) δ 171.6,163.9,151.8,151.5,142.1,139.6,136.6,135.3,134.6,132.5,130.6,130.4 (2), 130.1,129.2,129.1,122.6121.7117.9,117.7,100.1,73.7,68.9,68.7,40.0,30.0,29.7,22.2; EI-MS (m/z) 517 (M
+), HRMS C
33h
27nO
5[M
+], calculated value: 517.1889, measured value: 517.1890.
Embodiment 24.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 78mg light yellow solid Compound 24 according to the method for embodiment 1, yield 47% with 8-methoxyl group-2-n-propylamine base-Isosorbide-5-Nitrae naphthoquinones; 10mg light yellow solid Compound 39, yield 5%.
Compound 24:
1h NMR (300MHz, CDCl
3) δ 7.29 (m, 8H), 7.17 (m, 3H), 6.67 (d, J=8.2Hz, 1H), 6.42 (d, J=8.1Hz, 1H), 3.98 (s, 3H), 3.05 (q, J=7.6Hz, 2H), 1.50 (t, J=7.5Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 168.6,151.1,150.0,147.6,139.9,139.6,135.6,134.1,131.1,129.1,128.8,128.2,127.7,127.6,125.8,122.0,116.3,116.2,113.0,107.2,99.9,55.9,22.3,11.1; EI-MS (m/z) 419 (M
+), HRMSC
28h
21nO
3[M
+], calculated value: 419.1521, measured value: 419.1521.
Compound 39:
1h NMR300MHz, CDCl
3) δ 7.36 (m, 3H), 7.27 (m, 5H), (7.17 m, 3H), 6.70 (d, J=8.3Hz, 1H), 6.47 (d, J=8.2Hz, 1H), (6.20 q, J=6.7Hz, 1H), 3.98 (s, 3H), 2.19 (s, 3H), 1.81 (d, J=6.7Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 170.1,164.3,151.3,150.4,147.6,140.1,139.1,135.5,134.0,131.1,129.1,128.8,128.3,127.7,127.6,125.7,122.5,117.0,116.2,113.1,107.5,100.0,65.5,55.9,21.1,18.6; EI-MS (m/z) 477 (M
+), HRMS C
30h
23nO
5[M
+], calculated value: 477.1576, measured value: 477.1577.
Embodiment 25.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 91mg light yellow solid Compound 25 according to the method for embodiment 1, yield 46% with 8-benzyloxy-2-n-propylamine base-Isosorbide-5-Nitrae naphthoquinones; 18mg light yellow solid Compound 40, yield 8%.
Compound 25:
1h NMR (300MHz, CDCl
3) δ 7.64 (d, J=7.3Hz, 2H), 7.39 (m, 6H), 7.29 (m, 2H), 7.24 (m, 2H), (7.19 m, 4H), 6.75 (d, J=8.2Hz, 1H), 6.41 (d, J=8.2Hz, 1H), (5.24 s, 2H), 3.04 (q, J=7.5Hz, 2H), 1.49 (t, J=7.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 168.4,150.0 (2), 147.8,140.0,139.6,137.0,135.6,134.1,131.1,129.1,128.8,128.5,128.3,127.8,127.7,127.6,126.9,126.1,122.0,116.2,113.4,108.7,99.9,70.3,22.4,11.0; EI-MS (m/z) 495 (M
+), HRMS C
34h
25nO
3[M
+], calculated value: 495.1834, measured value: 495.1839.
Compound 40:
1h NMR (400MHz, CDCl
3) δ 7.68 (d, J=7.3Hz, 2H), 7.46 (t, J=7.5Hz, 2H), 7.40 (m, 4H), (7.33 m, 2H), 7.30 (d, J=1.6Hz, 1H), 7.28 (d, J=1.3Hz, 1H), 7.26 (s, 1H), 7.22 (m, 3H), (6.83 d, J=8.2Hz, 1H), 6.52 (d, J=8.2Hz, 1H), 6.24 (q, J=6.7Hz, 1H), 5.27 (s, 2H), 2.13 (s, 3H), 1.82 (d, J=6.8Hz, 3H);
13cNMR (126MHz, CDCl
3) δ 169.5,163.7,149.9,149.6,147.3,139.7,138.7,136.4,135.0,133.5,130.6,128.6,128.3,128.0,127.8,127.3,127.2,127.1,126.3,125.5,122.1,116.4,115.7,112.9,108.4,99.5,69.7,65.1,20.5,18.0; EI-MS (m/z) 553 (M
+), HRMS C
36h
27nO
5[M
+], calculated value: 553.1889, measured value: 553.1891.
Embodiment 26.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 151mg light yellow solid Compound 26 according to the method for embodiment 1, yield 86% with 2-n-propylamine base-Isosorbide-5-Nitrae anthraquinone.
1h NMR (300MHz, CDCl
3) δ 8.19 (s, 1H), 7.79 (d, J=8.1Hz, 1H), 7.27 (m, 3H), 7.22 (m, 6H), 7.16 (m, 2H), 7.05 (m, 2H), 6.77 (ddd, J=9.2,6.5,1.3Hz, 1H), 3.06 (
q, J=7.6Hz, 2H), 1.52 (t, J=7.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 167.8,153.2,150.8,140.3,138.9,137.3,134.6 (2), 131.4,129.3,128.9,128.6,128.3,127.7,127.4,126.9,126.0,123.7,122.9,121.3,118.8,117.5,115.9,96.5,22.4,11.3; EI-MS (m/z) 439 (M
+), HRMS C
31h
21nO
2[M
+], calculated value: 439.1572, measured value: 439.1570.
Embodiment 27.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 113mg light yellow solid Compound 27 according to the method for embodiment 1, yield 70% with 2-methyl-3-cyclopropyl methylamino--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (300MHz, CDCl
3) δ 7.57 (d, J=8.4Hz, 1H), 7.36 (m, 5H), 7.26 (d, J=8.5Hz, 2H), (7.19 m, 4H), 6.45 (d, J=7.3Hz, 1H), 3.04 (q, J=7.6Hz, 2H), 2.57 (s, 3H), 1.49 (t, J=7.6Hz, 3H);
13c NMR (126MHz, CDCl
3) δ 167.6,149.5,146.2,139.9,138.8,135.5,134.3,132.7,131.1,129.1,128.7,128.3,127.6,127.5,127.4,120.3,118.1,116.1,116.0,115.6,108.1,22.4,11.4,9.9; EI-MS (m/z) 403 (M
+), HRMS C
28h
21nO
2[M
+], calculated value: 403.1572, measured value: 403.1573.
Embodiment 28.
Except replacing, except 2-n-propylamine base-1,4-naphthoquinone, preparing 167mg light yellow solid Compound 28 according to the method for embodiment 1, yield 89% with 2-phenyl-3-cyclopropyl methylamino--Isosorbide-5-Nitrae naphthoquinones.
1h NMR (300MHz, CDCl
3) δ 7.87 (d, J=8.0Hz, 2H), 7.65 (d, J=8.3Hz, 1H), 7.48 (t, J=7.7Hz, 2H), 7.38 (m, 4H), 7.27 (m, 3H), 7.19 (d, J=7.9Hz, 2H), 7.10 (m, 3H), 6.52 (d, J=7.4Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 1.47 (t, J=7.5Hz, 3H);
13c NMR (101MHz, CDCl
3) δ 167.8,149.4,145.5,140.6,137.8,135.5,133.7,133.6,133.0,131.1,130.6,129.3,128.8,128.4,128.0,127.7,127.5,127.4,120.6,119.4,116.4,116.2,116.1,112.6,22.5,11.5; EI-MS (m/z) 465 (M
+), HRMS C
33h
23nO
2[M
+], calculated value: 4658.1729, measured value: 465.1727.
The biological activity of compound in cell proliferation growth-inhibiting that the present invention includes is set forth below by pharmacological evaluation.
Adopt KB, KB/VCR and A549 cell, add compound treatment 72h respectively, by the proliferate restraining effect of srb assay detection compound and degree thereof, (this experiment adopts testing method and equipment to be method and apparatus conventional in this area, agents useful for same is analytical pure or chemical pure, and cell used is same experiments conventional commercial cell).
Adopt srb assay, with TANSHINONES-I(Tan-I) be positive control, preliminary assessment compound, to the inhibited proliferation of KB, KB/VCR and A549 cell, the results are shown in Table 1.In experiment, compound adopts the highest final concentration 20 μMs, process cell 72 hours.
Table 1. compound is to the inhibited proliferation of KB, KB/VCR and A549 cell
Above embodiment is only enumerate as the example of embodiment of the present invention, does not form any restriction to the present invention, it will be appreciated by those skilled in the art that the amendment in the scope not departing from essence of the present invention and design all falls into protection scope of the present invention.
Claims (10)
1. novel tetracyclic naphthalene an oxazole analog derivative, it has the structure shown in following general formula (I):
Wherein,
X is O or S;
Y is O or S;
Z is C or N;
R
1and R
2independently but be not side by side hydrogen, be separately halogen atom, hydroxyl, C
1-C
6alkoxyl group, amino, C
1-C
6alkylamino, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl; Or, R
1and R
2substituted or unsubstituted C can be connected to form
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, C
1-C
10alkyl, halo C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl;
R
3and R
4be separately hydrogen, halogen atom, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl; Or, R
3and R
4substituted or unsubstituted C can be connected to form
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl;
R
5and R
7be separately hydrogen, halogen atom, replacement or do not replace C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, 3 to 6 yuan of oxa-s or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl;
R
6for hydrogen, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted thiazolinyl, halo C
1-C
6alkyl, substituted or unsubstituted C
3-C
10cycloalkyl, substituted or unsubstituted C
3-C
6oxa-or azacycloalkyl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl carbonyl oxygen base, monosubstituted, two replacement or non-substituted-amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6oxa-or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, wherein, substituting group is selected from C
1-C
6alkyl, C
1-C
6carbonyl, C
1-C
6alkoxy carbonyl.
2. novel tetracyclic Nai Bing oxazole analog derivative as claimed in claim 1, is characterized in that:
R
1and R
2be separately C
1-C
6alkoxy carbonyl, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted phenyl; Or, R
1and R
2substituted or unsubstituted phenyl can be connected to form; Wherein, substituting group is selected from halogen atom, carboxyl, C
1-C
6alkoxyl group, C
1-C
6alkyl or halo C
1-C
6alkyl.
3. novel tetracyclic Nai Bing oxazole analog derivative as claimed in claim 1, is characterized in that:
R
3and R
4be separately H, C
1-C
6alkoxy carbonyl, C
1-C
6amido, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or C
1-C
6alkylamino; Or, R
3and R
4substituted or unsubstituted phenyl can be connected to form; Wherein, substituting group is selected from halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or phenyl.
4. novel tetracyclic Nai Bing oxazole analog derivative as claimed in claim 1, is characterized in that:
R
5and R
7be separately H, replacement or do not replace C
1-C
6alkoxyl group, C
1-C
6amido, substituted or unsubstituted C
1-C
10alkyl, substituted or unsubstituted C
6-C
10aryl; Wherein, substituting group is selected from halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group or phenyl.
5. novel tetracyclic Nai Bing oxazole analog derivative as claimed in claim 1, is characterized in that:
X is O;
Y is O;
Z is N;
R
1and R
2be separately substituted or unsubstituted C
1-C
6alkyl or phenyl, C
6-C
10aryl or five yuan or six membered heteroaryl; Wherein, substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
1-C
6alkoxyl group, C
1-C
6alkylamino;
R
3and R
4be separately H, halogen atom, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl, C
1-C
6alkoxyl group or C
1-C
6alkylamino; Or, R
3and R
4naphthalene nucleus can be connected to form;
R
5and R
7be separately H, halogen atom, C
1-C
6alkoxy carbonyl, substituted or unsubstituted C
1-C
6alkyl or phenyl, replacement or do not replace C
1-C
6alkoxyl group or C
1-C
6alkylamino; Wherein, substituting group is selected from halogen atom, hydroxyl, amino, C
6-C
10aryl or five yuan or six membered heteroaryl;
R
6for hydrogen, substituted or unsubstituted C
1-C
6alkyl, substituted or unsubstituted thiazolinyl; Substituting group is selected from halogen atom, hydroxyl, carboxyl, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl carbonyl oxygen base, monosubstituted, two replacement or non-substituted-amino, C
1-C
6amido, nitro, cyano group, C
1-C
6alkyl, halo C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6oxa-or azepine cycloaliphatic ring, C
1-C
6alkoxyl group, C
1-C
6alkylamino, C
6-C
10aryl or five yuan or six membered heteroaryl, wherein, substituting group is selected from C
1-C
6alkyl, C
1-C
6carbonyl, C
1-C
6alkoxy carbonyl.
6. novel tetracyclic Nai Bing oxazole analog derivative as claimed in claim 1, it is characterized in that, described derivative is selected from the compound with one of following structural formula:
7. prepare a method for derivative as claimed in claim 1, it is synthesized by following route:
2-substituted-amino quinones is activated by C-H the cascade reaction participated in replacement alkynes and forms target compound (I), reaction formula is as follows:
Wherein, activate 5 of quinones with metal catalyst Rh, and add oxygenant Cu (OAc)
2.H
2o and additive A gSbF
6, Reactive Synthesis in solvent t-AmOH.
8. method according to claim 7 prepares a method for compound as claimed in claim 6, and its reaction formula is:
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
9. novel tetracyclic Nai Bing oxazole analog derivative according to claim 1 is as the application of cytostatic agent.
10. novel tetracyclic Nai Bing oxazole analog derivative according to claim 1 is preparing the application in antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010068837A (en) * | 2000-01-10 | 2001-07-23 | 구광시 | Anti-cancer agent containing masonone E from family Ulmaceae |
| CN101220035A (en) * | 2008-01-15 | 2008-07-16 | 中山大学 | A kind of alkaloid, method for preparing the same and application in antineoplastic or antimicrobial aspects |
-
2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010068837A (en) * | 2000-01-10 | 2001-07-23 | 구광시 | Anti-cancer agent containing masonone E from family Ulmaceae |
| CN101220035A (en) * | 2008-01-15 | 2008-07-16 | 中山大学 | A kind of alkaloid, method for preparing the same and application in antineoplastic or antimicrobial aspects |
Non-Patent Citations (1)
| Title |
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| HUA-PEI JIAN,等: "A FACILE SYNTHESIS OF NOVEL HETEROPOLYCYCLIC PYRAZINES AND OXAZOLES AND MECHANISTIC STUDIES OF 2，3-DIHYDROBENZO[de]CHROMENE-7，8-DIONE WITH AMINES", 《HETEROCYCLES》 * |
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| CN112770735A (en) * | 2018-07-29 | 2021-05-07 | Musc研究发展基金会 | Compounds for the treatment of neurological or mitochondrial diseases |
| US11771685B2 (en) | 2018-07-29 | 2023-10-03 | Musc Foundation For Research Development | Compounds for the treatment of neurological or mitochondrial diseases |
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