CN107434781A - A kind of preparation method and applications of 1- alkenyls-isoquinilone derivatives - Google Patents
A kind of preparation method and applications of 1- alkenyls-isoquinilone derivatives Download PDFInfo
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- CN107434781A CN107434781A CN201610357333.9A CN201610357333A CN107434781A CN 107434781 A CN107434781 A CN 107434781A CN 201610357333 A CN201610357333 A CN 201610357333A CN 107434781 A CN107434781 A CN 107434781A
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- alkenyls
- isoquinilone derivatives
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- halogen
- isoquinilone
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- OPUVMUVTNJDESG-VOTSOKGWSA-N COC(/C=C/c1nccc2ccccc12)=O Chemical compound COC(/C=C/c1nccc2ccccc12)=O OPUVMUVTNJDESG-VOTSOKGWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention belongs to medicinal chemistry art, is related to a kind of preparation method and applications of the alkenyl isoquinilone derivatives of antitumoral compounds 1, the present invention is using isoquinoline nitrogen oxide in PdCl2Catalysis under and olefin(e) compound occur coupling reaction obtain following structure.1 alkenyl isoquinilone derivatives provided by the invention show excellent antitumor activity to kinds of tumor cells, can be as the candidate or lead compound further developed, applied to preparing cancer therapy drug.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to the preparation method of a kind of 1- alkenyls-isoquinilone derivatives, and application of such compound as a kind of new antineoplastic lead compound.
Background technology
Medically cancer refers to the malignant tumour originating from epithelial tissue, be body under the effect of various tumorigenesis factors, local organization cell loses the neoformation for causing paraplasm with differentiation to the normal regulation that it grows and being formed on gene level.Neoformation, not by normal body Physiological effect, destroys normal structure and organ, this point is especially apparent in malignant tumour once being formed.Malignant growth speed is fast, and bleeding, necrosis, ulcer etc. easily occurs, and often has DISTANT METASTASES IN, causes human body to become thin, be powerless, anaemia, poor appetite, heating and serious organ function are impaired etc., ultimately causes death.
Compound with isoquinolin skeleton is widely present in natural products and the molecule of bioactivity, and representational compound is such as：The alkaloids such as Papaverine, Berberine, Oxoglaucine, Sanguinarine, Ungeremine and Dicentrinone.From the morphinane alkaloid skeleton of nature separation, Pharmaceutical Chemist designs and artificial synthesized many derivatives containing isoquinolin skeleton, with many important physiologically actives, discovery to new drug has important value, such as 2006, Markmee et al. (Bioorg.Med.Chem.Lett 2006, 16, 2170) it is found that activity of the isoquinilone derivatives as AchE inhibitor, the same year Trotter (J.Med.Chem.2006, 49, 6954) a series of isoquinilone derivatives of 3- cyano group substitutions are designed and synthesized, respectively by testing its inhibitory activity to Kv1.5 potassium-channels in vivo and in vitro, for treating new house vibration.2010, the isoquinoline compound of the synthesis such as song (J.Med.Chem.2010,53,1979) had preferable therapeutic effect to leukaemia, oophoroma, breast cancer etc..
In isoquinoline compound, the isoquinoline compound of 1- alkenyls substitution due to its unique structure there is more bioactivity to be worth.Such as it is used as antibacterial, cancer therapy drug and enzyme inhibitor (Bioorg.Med.Chem.Lett 2010,20,7331；Org.Biomol.Chem., 2012,10,1239.), the traditional synthetic method of 1- alkenyl isoquinolin occurs nucleophilic addition with aldehyde or imines typically by 1- methylisoquinoliniums compound and obtained, but because substituted 1- methylisoquinoliniums are expensive and are not readily available, limit the application of these methods.The simple efficient route of design obtains 1- alkenyls isoquinoline compound to studying new type antineoplastic medicine from the raw material synthesis being easy to get, and medicine of developing one's own intellectual property is significant.
The content of the invention
The purpose of the present invention is from isoquinoline nitrogen oxide simple and easy to get, there is provided synthesis obtains 1- alkenyls-isoquinilone derivatives, it is characterised in that such compound has structure as shown below,
Wherein R1For different the position of substitution, the alkyl of different numbers, aryl, alkoxy, aryloxy group, halogen, trifluoromethyl at least one, R2For alkyl, aryl, ester group, heteroaryl at least one.
In formula preferably：R1For the mono-substituted C1-C5 of diverse location alkyl, alkoxy, halogen, trifluoromethyl or polysubstituted halogen, R2For 4- chlorphenyls, pyridine radicals.
It is another object of the present invention to provide a kind of 1- alkenyls-isoquinilone derivatives preparation method, it is characterised in that：It is achieved by the steps of：
In organic solvent, add isoquinoline nitrogen oxide and olefin(e) compound react in the presence of palladium chloride, obtain following target product,
Catalyst used is one kind in palladium chloride, palladium trifluoroacetate, the triphenylphosphine palladium of dichloro two, and solvent is dimethyl sulfoxide, and for reaction temperature at 100 DEG C -120 DEG C, the time is 20-30 hours.
3rd, it is yet a further object of the present invention to provide application of the compound in antineoplastic is prepared.
Embodiment
The embodiment of the present invention is described in detail, it is necessary to explain below, embodiment described herein is merely to illustrate and explain the present invention, and is not intended to limit the invention.
On the one hand, it is an object of the invention to provide synthesize a kind of 1- alkenyls-isoquinilone derivatives, it is characterised in that and such compound has structure as shown below,
Wherein R1For at least one of different the position of substitution, the alkyl of different numbers, aryl, alkoxy, aryloxy group, halogen, trifluoromethyl, R2For alkyl, aryl, ester group, heteroaryl at least one.
In the present invention, alkyl is preferably C1-C5 alkyl, and alkoxy is preferably C1-C5 alkoxy, and aryloxy group is preferably C6-C10 aryloxy group, and ester group is preferably C1-C5 ester group.
1- alkenyls-isoquinilone derivatives of the present invention are more preferably R2It is as follows for 4- chlorphenyls, pyridine radicals：
On the other hand, process provides a kind of method of convenient synthesis 1- alkenyls-isoquinilone derivatives.Including：
1 in organic solvent, adds isoquinoline nitrogen oxide and olefin(e) compound reacts to obtain 1- alkenyls-isoquinilone derivatives in the presence of palladium chloride.
In 2 the inventive method, step 1 using palladium trifluoroacetate, the triphenylphosphine palladium of dichloro two except using palladium chloride, also can obtain product, but yield is relatively low.Solvent is in addition to using dimethyl sulfoxide, and using DMF, 1-METHYLPYRROLIDONE also can obtain product, but yield is relatively low.
In 3 the inventive method, step 1 reaction condition includes, 100-120 DEG C of temperature, and the time is 20-30 hours；Products therefrom obtains net product through the purification such as column chromatography or recrystallization；Recrystallization solvent for use is the mixture of acetone, ethanol, methanol, one kind in ethyl acetate or two of which.
Another further aspect, the invention provides such as above-mentioned 1- alkenyls-isoquinilone derivatives antitumor activity evaluation test result in vitro, for DU145 prostate cancers, MCF7 breast cancer, EC109 esophageal squamous cell carcinomas, MGC803 stomach cancers have obvious inhibiting effect, and wherein compound 4 and the antitumor activity of 7 pairs of breast cancer and stomach cancer is substantially better than 5-fluor-uracil, can be as the candidate or lead compound further developed, applied to preparing antineoplastic.
Method is exemplified below：
Prepare following compound：
The 1- styryls of compound 1-isoquinolin
Isoquinoline N-oxides (72mg, 0.5mmol), styrene (525mg, 2.5mmol), PdCl2(8.8mg, 0.05mmol) and 1mL dimethyl sulfoxide (DMSO)s 100 DEG C of stirring reactions 20 hours in 5mL reaction tube, then add 20mL ethyl acetate, successively using saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying.Concentration, column chromatography (ethyl acetate/petroleum ether=1: 8) obtain faint yellow solid 88.5mg, total recovery 77%.1H NMR (400MHz, CDCl3) δ 7.35 (t, J=7.2Hz, 1H), 7.43 (t, J=7.2Hz, 2H), 7.58 (d, J=5.6Hz, 1H), 7.63-7.72 (m, 4H), 7.84 (d, J=8.0Hz, 1H), 8.00 (d, J=3.6Hz, 2H), 8.38 (d, J=8.4Hz, 1H), 8.57 (d, J=5.6Hz, 1H)13C NMR (100MHz, CDCl3) δ 120.1,123.0,124.6,126.9,127.3,127.5,127.6,128.8,128.9,130.1,136.1,136.9,137.1,142.6,154.7
The 1- of compound 2 (4- methoxyl groups) styryl-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 60%.1H NMR (400MHz, DMSO-d6) δ 3.82 (s, 3H), 7.01 (d, J=8.8Hz, 2H), 7.69-7.73 (m, 2H), 7.78 (t, J=6.8Hz, 1H), 7.84 (d, J=8.4Hz, 2H), 7.95-7.99 (m, 2H), 8.13 (d, J=15.6Hz, 1H), 8.52 (d, J=5.6Hz, 1H), 8.70 (d, J=8.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 55.2,114.2,119.4,120.4,124.8,126.0,127.1,127.3,129.2,130.1,134.9,136.3,142.3,154.1,159.8
The 1- of compound 3 (2- chlorine) styryl-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 72%.1H NMR (400MHz, DMSO-d6) δ 7.40 (td, J=2.0,7.6Hz, 1H), 7.46 (t, J=6.4Hz, 1H), 7.54 (dd, J=1.2,8.0Hz, 1H), 7.72-7.82 (m, 3H), 8.00 (d, J=8.4Hz, 1H), 8.29 (dd, J=1.2,8.0Hz, 1H), 8.36 (s, 2H), 8.59 (d, J=6.4Hz, 1H), 8.72 (d, J=8.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 120.4,124.8,125.8,126.3,127.2,127.5,127.6,127.8,129.8,130.0,130.1,130.3,133.2,134.1,136.3,142.4,153.2
The 1- of compound 4 (4- chlorine) styryl-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 53%.1H NMR (400MHz, DMSO-d6) δ 7.51 (d, J=8.0Hz, 2H), 7.71-7.82 (m, 3H), 7.93-8.00 (m, 4H), 8.32 (d, J=15.6Hz, 1H), 8.54 (d, J=5.2Hz, 1H), 8.73 (d, J=8.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 120.1,123.8,124.8,126.2,127.1,127.5,128.7,129.4,130.2,133.0,133.7,135.5,136.3,142.3,153.5
The 1- of compound 5 (4- fluorine) styryl-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 63%.1H NMR (400MHz, DMSO-d6) δ 7.29 (d, J=9.2Hz, 2H), 7.70-7.82 (m, 3H), 7.95-8.01 (m, 4H), 8.25 (d, J=15.2Hz, 1H), 8.54 (d, J=5.6Hz, 1H), 8.72 (d, J=8.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 115.6 (d, JF=21.5Hz), 119.9,122.8 (d, JF=2.3Hz), 124.8,126.1,127.1,127.5,129.8 (d, JF=7.5Hz), 130.2,133.1 (d, JF=3.1Hz), 133.9,136.3,142.2,153.7,162.2 (d, JF=244.8Hz)
The 1- naphthalene vinyls of compound 6-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 61%.1H NMR (400MHz, DMSO-d6) δ 7.53-7.57 (m, 2H), 7.73-7.83 (m, 3H), 7.94-8.01 (m, 4H), 8.15-8.22 (m, 2H), 8.28 (s, 1H), (8.44 d, J=15.2Hz, 1H), (8.57 d, J=5.6Hz, 1H), 8.79 (d, J=8.0Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 119.9,123.3,124.5,124.9,126.2,126.5,126.5,127.2,127.5,127.6,128.1,128.2,128.2,130.2,133.1,133.3,134.2,135.1,136.3,142.4,153.7
The 1- pyridines vinyl of compound 7-isoquinolin
Synthetic method is the same as compound 1, yellow solid, yield 79%.1H NMR (400MHz, DMSO-d6) δ 7.37 (q, J=4.4Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.80-7.83 (m, 2H), 7.87 (d, J=4.0Hz, 2H), 8.00-8.04 (m, 2H), 8.57-8.65 (m, 3H), 8.68 (d, J=4.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 120.5,123.2,123.5,124.4,126.1,126.4,127.3,127.8,130.3,134.7,136.2,136.9,142.4,149.7,153.1,154.5
The 3- isoquinolyl methyl acrylates of compound 8
Synthetic method is the same as compound 1, yellow solid, yield 31%.1H NMR (400MHz, DMSO-d6) δ 3.81 (s, 3H), 7.13 (d, J=15.2Hz, 1H), 7.74-7.78 (m, 1H), 7.83 (td, J=1.2,6.8Hz, 1H), 7.93 (d, J=4.8Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 8.48 (d, J=8.4Hz, 1H), 8.54 (d, J=15.6Hz, 1H), 8.62 (d, J=4.8Hz, 1H)13C NMR (100MHz, DMSO-d6) δ 51.8,122.4,123.9,124.1,126.7,127.4,128.4,130.6,136.2,138.4,142.5,150.8,166.3
Test case
Choose compound 2-7 obtained above and carry out following determination of activity
Experiment material：
1 man―machine systems：It is purchased from Chinese Academy of Sciences's Shanghai cell bank.
2 test medicines：After being dissolved with DMSO, 10000 micrograms per millilitre initial concentrations are configured to, it is standby.
3 0.9% physiological saline：Lot number 201521112, specification 250mL：2.25g, Zhengzhou Yonghe Pharmaceutical Co's product.
45 FU 5 fluorouracil parenteral solutions (5-Fu), lot number 140107, specification 10mL：0.25g/ branch, Shanghai Xudong Hipu Medicine Co., Ltd's product.
Experimental method
Cell routine is inoculated in complete medium, through 37 DEG C, 5% CO2Saturated humidity culture, amplification.Cell is for experiment with after 0.25% Trypsin Induced, adding nutrient solution to be diluted to 1 × 105/mL tumor cell suspensions (tire expects blue dyeing, the equal ＞ 95% of viable count).In setting negative control hole and Positive control wells, test sample various concentrations hole on 96 hole sterile culture plates, concentration is set as 64,32,16,8,4,2,1,0.5 micrograms per millilitre, while each concentration sets 3 multiple holes.The cell suspension inoculation prepared is added to the compound of various concentrations after 96 hole sterile culture plates, culture 24h.The nutrient solution of equivalent is added in negative control hole, inserts in incubator and cultivates.Taken out after 72h, the μ L of MTT 20 are added per hole, continued to cultivate 4h, centrifuged after taking-up, supernatant is abandoned in suction.DMSO150 μ L are added per hole, concussion is completely dissolved the crystallization of hyacinthine first a ceremonial jade-ladle, used in libation.The OD values in each hole are determined with ELIASA, its IC is calculated by SPSS50。
Experimental result
Antitumor activity evaluation data of the above-claimed cpd to four kinds of human tumor cells
Test result indicates that：Compound 4 and 7 shows excellent antitumor activity, is better than 5-fluor-uracil to MGC803 stomach cancers and the inhibitory activity of MCF7 breast cancer cells, can be as the candidate or lead compound further developed, applied to preparing cancer therapy drug.
Claims (4)
1. a kind of 1- alkenyls-isoquinilone derivatives, it has structure as shown below, wherein R1For different the position of substitution, the alkyl of different numbers, aryl, alkoxy, aryloxy group, halogen, trifluoromethyl at least one, R2For alkyl, aryl, ester group, heteroaryl at least one.
2. 1- alkenyls-isoquinilone derivatives as claimed in claim 1, it is characterised in that preferably：R1For the mono-substituted C1-C5 of diverse location alkoxy, halogen, trifluoromethyl or polysubstituted halogen, R2For 4- chlorphenyls, pyridine radicals.
A kind of 3. preparation method of 1- alkenyls-isoquinilone derivatives, it is characterised in that：It is achieved by the steps of：
In organic solvent, add isoquinoline nitrogen oxide and olefin(e) compound react in the presence of palladium chloride, obtain following target product,
Catalyst used is one kind in palladium chloride, palladium trifluoroacetate, the triphenylphosphine palladium of dichloro two, and solvent is dimethyl sulfoxide, and for reaction temperature at 100 DEG C -120 DEG C, the time is 20-30 hours.
4. 1- alkenyls-application of the isoquinilone derivatives in medicine is prepared in claim 1-2 described in any one, it is characterised in that as active component, be prepared into anti-prostate cancer, esophageal squamous cell carcinoma, stomach cancer, breast cancer medicines.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480520A (en) * | 2021-08-16 | 2021-10-08 | 吉林大学 | Isoquinoline-1, 3(2H,4H) -diketone derivative and application thereof |
| CN114409595A (en) * | 2022-01-11 | 2022-04-29 | 南华大学附属第一医院 | 1-styryl isoquinoline derivative and preparation and application thereof |
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| EP0151319A1 (en) * | 1981-03-24 | 1985-08-14 | Eli Lilly And Company | Hexahydrobenzo[de]quinoline derivatives and their preparation |
| EP0680953A1 (en) * | 1994-05-03 | 1995-11-08 | Egis Gyogyszergyar Rt. | 1-[Styryl]- and 1-[2'-(heteroaryl)-ethenyl]-isoquinoline derivatives, a process for preparing them as well as medicaments containing them and the use of them |
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2016
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Patent Citations (2)
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| EP0151319A1 (en) * | 1981-03-24 | 1985-08-14 | Eli Lilly And Company | Hexahydrobenzo[de]quinoline derivatives and their preparation |
| EP0680953A1 (en) * | 1994-05-03 | 1995-11-08 | Egis Gyogyszergyar Rt. | 1-[Styryl]- and 1-[2'-(heteroaryl)-ethenyl]-isoquinoline derivatives, a process for preparing them as well as medicaments containing them and the use of them |
Non-Patent Citations (5)
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| BAHNER, CARL TABB: "Effects of variations in chemical structure on antitumor activity and toxicity of styrylquinolines and similar compounds", 《ACTA UNIO INTERNATIONALIS CONTRA CANCRUM》 * |
| CHODKOWSKI, JERZY等: "Polarographic behavior of isomeric pyridyl-vinylquinolines and pyridyl-vinylisoquinolines. I.2-Quinolyl and 1-isoquinolyl derivatives", 《ROCZNIKI CHEMII》 * |
| FOZARD, ALAN等: "New tetracyclic systems incorporating the benzo[c]quinolizinium cation", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| TAYLOR, EDWARD C.等: "Nucleophilic displacement of primary amino groups via 1-substituted 4-tosylimidazoles", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480520A (en) * | 2021-08-16 | 2021-10-08 | 吉林大学 | Isoquinoline-1, 3(2H,4H) -diketone derivative and application thereof |
| CN113480520B (en) * | 2021-08-16 | 2022-05-13 | 吉林大学 | Isoquinoline-1, 3(2H, 4H) -diketone derivative and application thereof |
| CN114409595A (en) * | 2022-01-11 | 2022-04-29 | 南华大学附属第一医院 | 1-styryl isoquinoline derivative and preparation and application thereof |
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Application publication date: 20171205 |