CN110172037A - A kind of pyridine structure contained styrylpyridinium compound, preparation method and its application for preparing anti-tumor drug - Google Patents

A kind of pyridine structure contained styrylpyridinium compound, preparation method and its application for preparing anti-tumor drug Download PDF

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CN110172037A
CN110172037A CN201910583916.7A CN201910583916A CN110172037A CN 110172037 A CN110172037 A CN 110172037A CN 201910583916 A CN201910583916 A CN 201910583916A CN 110172037 A CN110172037 A CN 110172037A
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pyridine
preparation
structure contained
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孙武积
朱皓
钟启迪
庄鹏宇
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North China University of Science and Technology
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North China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Abstract

The invention belongs to field of medicaments, and in particular to a kind of pyridine structure contained styrylpyridinium compound, preparation method and its application for preparing anti-tumor drug, the compound are with such as I compound represented of general formula.Compound of the present invention with general formula I has preferable inhibitory activity to non-small cell lung cancer A549 and hepatocellular carcinoma H22, can be used for preparing anti-tumor drug, especially suitable for tumours such as liver cancer, kidney, lung cancer, thyroid cancer, colon cancers.

Description

A kind of pyridine structure contained styrylpyridinium compound, preparation method and its preparation The application of anti-tumor drug
Technical field
The invention belongs to pharmaceutical compound fields, and in particular to the pyridine structure contained styrylpyridinium compound of one kind, system Preparation Method and its application for preparing anti-tumor drug.
Background technique
In recent decades, with the change of human lives' habit and living environment, rise is presented always in the disease incidence of cancer Trend, becoming leads to one of Important cause of disease of human death.The World Health Organization has delivered " 2017 world healths statistics report Accuse ", there are about 40,000,000 people to die of non-communicable diseases every year in the report display whole world, wherein 8,800,000 die of cancer.China is annual New cancer cases are up to 4,290,000 people, and the 20% of Zhan Quanqiu new cases, death is up to 2,810,000.Cancer prevents and treats Treatment has become important one of the public health problem in China.
With deepening continuously for molecular biology and RESEARCH ON CELL-BIOLOGY, people further recognize Tumorigenesis Know, has developed different kinds of molecules target therapeutic agent.Molecular targeted therapy is key from being directed to during growth and metastasis of tumours The target molecule and associated signal paths of effect, interfere or block its function, achieve the purpose that inhibit growth and metastasis of tumours.Tumour Molecular targeted therapy has high selectivity, and drug or inhibitor enter can make in conjunction with corresponding carcinogenic site in vivo With keeping tumor cell specific dead, without involving other normal tissue cells.Currently, the blood vessel based on angiogenesis Endothelial growth factor receptor VEGFR-2 is received more and more attention, and has had the VEGFR-2 of different types of structure to inhibit Agent is reported.In short, with the development of molecular biology, treatment of cancer comes into the targeted therapy epoch, target is further researched and developed Strong, efficient, low toxicity the new anticancer drug of tropism, has become the important directions of current anti-tumor drug research.
Summary of the invention
The purpose of the present invention is to provide a kind of pyridine structure contained styrylpyridinium compound and preparation method thereof, this Class compound belongs to novel VEGFR-2 inhibitor, shows good inhibition to the VEGFR-2 tumour cell being overexpressed in vitro Activity.
The present invention also provides pyridine structure contained styrylpyridinium compound (general formula I) answering in anti-tumor drug With.
The following technical solution is employed by the present invention: a kind of pyridine structure contained styrylpyridinium compound, wherein described Pyridine structure contained styrylpyridinium compound has logical structure shown in formula I
Pyridine structure contained styrylpyridinium compound preparation method with general formula I the following steps are included:
Step 1: every preparation one unit 2- (4- nitrostyrolene base) pyridine (3) uses following steps: by 10mmol 2- Picoline (1), 10mmol 4- hydroxy benzaldehyde (2) mixing 20mmol acetic anhydride and 2mmol acetic acid are added in single port bottle, connect Entering anhydrous calcium chloride drying tube, be heated to vigorous reflux, continues back flow reaction about for 24 hours, TLC monitors end of reaction, it is concentrated under reduced pressure, The dissolution of 30mL methylene chloride is added in residue, and reaction solution successively uses 20% sodium bicarbonate aqueous solution and distillation water washing, anhydrous sulphur Sour sodium dries, filters, and is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains yellow solid 2.04g, yield 90%；
Step 2: every preparation one unit 2- (4- aminostyryl) pyridine (4) uses following steps: by 9mmol 2- (4- nitrostyrolene base) pyridine (3) is dissolved in 20mL ethyl alcohol, and the ammonium chloride solution of 20mL 4mol/L is added, adds 40mmol iron powder, is heated to 50 DEG C, and TLC monitors end of reaction, filtering, filtrate concentration, and ethyl acetate extracts repeatedly, organic phase without Aqueous sodium persulfate is dry, is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains yellow solid 1.53g, yield 86%；
Step 3: one unit 4- chloropyridine -2- acyl chlorides (6) of every preparation uses following steps: by 0.1mL anhydrous DMF and 20mL thionyl chloride is added in single port bottle, is passed through nitrogen protection, is heated to 50 DEG C, reacts 10min, 60mmol is then added portionwise 2- pyridine carboxylic acid (5), is heated to flowing back, and continues back flow reaction about 17h, and TLC monitors end of reaction, and 20mL dilution with toluene is added, It is concentrated under reduced pressure, repeats the operation twice, obtain brown oil 10.28g, yield 97%；
Step 4: one unit 4- Chloro-2-Pyridyle Carbox amide (8) of every preparation uses following steps: by 10mmol Organic amine compound (7) is dissolved in 15mL methylene chloride, and temperature control is at 0 DEG C or so, 10mmol 4- chloropyridine -2- acyl chlorides (6) it is dissolved in 15mL methylene chloride, is slowly added dropwise into organic amine compound (7) solution, reacts about 3h, TLC monitoring at room temperature End of reaction, reaction solution saturated common salt water washing, anhydrous sodium sulfate dry, filter, and recrystallization from ethyl acetate/petroleum ether obtains To 4- Chloro-2-Pyridyle Carbox amide (8)；
Step 5: the pyridine structure contained styrylpyridinium compound (I) of one unit of every preparation uses following steps: will 1mmol 2- (4- aminostyryl) pyridine (4) and 1mmol 4- Chloro-2-Pyridyle Carbox amide (8) are dissolved in 20mL second In nitrile, 1mmol zinc nitrate is added, is passed through nitrogen protection, is heated to flowing back, keep thermotonus, TLC monitors end of reaction, subtracts The dilution of 30mL ethyl acetate is added in pressure concentration, and reaction solution saturated common salt water washing, anhydrous sodium sulfate dries, filters, acetic acid second Ester/petroleum ether recrystallization, obtains pyridine structure contained styrylpyridinium compound (I).
Further: the R is selected from unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, alkane Base.The unsubstituted aryl is phenyl.The substituted aryl is the phenyl replaced selected from following group, comprising: halogen, alkane Oxygroup.The unsubstituted benzyl is benzyl.The substituted benzyl is the benzyl replaced selected from following group, comprising: alcoxyl Base, halogen；The alkyl is selected from methyl, isopropyl, cyclopropyl, cyclohexyl.
Pyridine structure contained styrylpyridinium compound with general formula I is in the application for preparing anti-tumor drug.
The further anti-tumor drug be suitable for liver cancer, kidney, lung cancer, thyroid cancer, colon cancer it is antitumor Drug.
The invention has the advantages that: use CCK-8 method to determine above compound to non-small cell lung cancer A549 and liver cancer The inhibiting effect of cell HepG2, the results showed that above compound has preferable inhibiting rate, part of compounds suppression to tumour cell System activity is more excellent than positive control drug Sorafenib, and the research and development for novel anti-tumor drug provide experiment basis.
Detailed description of the invention
Fig. 1: the present invention has the preparation route figure of the pyridine structure contained styrylpyridinium compound of general formula I.
Specific embodiment
Below with reference to embodiment, the invention will be further described, but the present invention is not limited to following embodiments.
A kind of pyridine structure contained styrylpyridinium compound, wherein the pyridine structure contained stibazole Compound has logical structure shown in formula IPreparation process refers to Fig. 1.
Embodiment 1
The preparation method of N- methyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -1:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- picoline 1 (0.93g, 10mmol), 4- hydroxy benzaldehyde 2 (1.51g, 10mmol) are mixed into acetic anhydride (2.04g, 20mmol) and acetic acid (0.12g, 2mmol) are added in single port bottle, access anhydrous calcium chloride drying tube, are heated to acutely Reflux continues back flow reaction about for 24 hours, and TLC monitors end of reaction, is concentrated under reduced pressure, and methylene chloride (30mL) dissolution is added in residue, Reaction solution is successively washed with 20% sodium bicarbonate aqueous solution (30mL) and distilled water (20mL × 2), and anhydrous sodium sulfate is dry, mistake Filter, is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains yellow solid 2.04g, yield 90%.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- nitrostyrolene base) pyridine 3 (2.04g, 9mmol) is dissolved in 20mL ethyl alcohol, the chlorination of 4mol/L is added Ammonium salt solution (20mL) adds iron powder (2.24g, 40mmol), is heated to 50 DEG C, and TLC monitors end of reaction, filters, and filtrate is dense Contracting, ethyl acetate extract (20mL × 3) repeatedly, and organic phase anhydrous sodium sulfate is dry, are concentrated under reduced pressure, and ethyl alcohol recrystallization obtains Huang Color solid 1.53g, yield 86%.
1H NMR(400MHz,DMSO-d6)δ:8.48(d,1H),7.70(t,1H),7.49(d,1H),7.42(d,1H), 7.33(d,2H),7.14(dd,1H),6.94(d,1H),6.59(d,2H),5.42(s,2H).
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
Anhydrous DMF (0.1mL) and thionyl chloride (20mL) are added in single port bottle, nitrogen protection is passed through, is heated to 50 DEG C, 10min is reacted, 2- pyridine carboxylic acid 5 (7.39g, 60mmol) is then added portionwise, is heated to flowing back, continues back flow reaction about 17h, TLC monitors end of reaction, and toluene (20mL) dilution is added, is concentrated under reduced pressure, repeats the operation twice, obtains brown oil 10.28g yield 97%.
The preparation of step 4 N- methyl -4- Chloro-2-Pyridyle formamide 8-1:
Methylamine 7-1 (0.31g, 10mmol) is dissolved in 15mL methylene chloride, temperature is controlled at 0 DEG C or so, is slowly added dropwise The dichloromethane solution (15mL) of 4- chloropyridine -2- acyl chlorides 6 (1.75g, 10mmol), is added dropwise, reacts about 3h at room temperature, TLC monitors end of reaction, and reaction solution is washed with saturated salt solution (30mL × 2), and anhydrous sodium sulfate dries, filters, and ethyl acetate/ Petroleum ether recrystallization, obtains yellow solid 1.38g, yield 81%.
1H NMR(400MHz,CDCl3)δ:8.40(d,1H),8.17(d,1H),7.98(s,1H),7.39(dd,1H), 3.01(d,3H).
The preparation of step 5 N- methyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -1:
By 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- methyl -4- Chloro-2-Pyridyle formamide 8-1 (170mg, 1mmol) is dissolved in 20mL acetonitrile, is added zinc nitrate (297mg, 1mmol), is passed through nitrogen protection, is heated to flowing back, Thermotonus is kept, TLC monitors end of reaction, is concentrated under reduced pressure, and ethyl acetate (30mL) dilution, reaction solution saturated common salt is added Water (25mL × 3) washing, anhydrous sodium sulfate dry, filter, and recrystallization from ethyl acetate/petroleum ether obtains brown solid 178mg, Yield 54%.
1H NMR(400MHz,DMSO-d6)δ:9.24(s,1H),8.67(d,1H),8.57(d,1H),8.26(d,1H), 7.80-7.75(m,1H),7.69-7.64(m,4H),7.52(d,1H),7.26-7.21(m,4H),7.11(dd,1H),2.80 (d,3H).
Embodiment 2
The preparation method of N- phenyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -2:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- phenyl -4- Chloro-2-Pyridyle formamide 8-2:
According to 1 step 4 of embodiment, methylamine 7-1 (0.31g, 10mmol) is replaced with into aniline 7-2 (0.93g, 10mmol), White solid 1.81g, yield 78% is made.
1H NMR(400MHz,CDCl3)δ:9.93(s,1H),8.54(d,1H),8.32(d,1H),7.78(d,2H),7.51 (dd,1H),7.42(t,2H),7.19(t,1H).
The preparation of step 5 N- phenyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -2:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- phenyl -4- Chloro-2-Pyridyle formamide 8-2 (233mg, 1mmol) is raw material, and yellow solid 232mg, yield 59% is made.
1H NMR(400MHz,CDCl3)δ:10.04(s,1H),8.65(d,1H),8.49(d,1H),7.87(d,1H), 7.78(d,2H),7.73-7.66(m,4H),7.43-7.38(m,3H),7.21-7.11(m,6H),7.07(dd,1H).
Embodiment 3
The preparation of N- (4- methoxyphenyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -3 Method:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- (4- methoxyphenyl) -4- Chloro-2-Pyridyle formamide 8-3:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with 4- aminoanisole 7-3 (1.23g, 10mmol), yellow solid 1.87g, yield 71% is made.
1H NMR(400MHz,CDCl3)δ:9.82(s,1H),8.52(d,1H),8.31(d,1H),7.70(d,2H),7.49 (dd,1H),6.95(d,2H),3.84(s,3H).
Step 5 N- (4- methoxyphenyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -3 Preparation:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- (4- methoxyl group Phenyl) -4- Chloro-2-Pyridyle formamide 8-3 (263mg, 1mmol) be raw material, be made yellow solid 224mg, yield 53%.
1H NMR(400MHz,CDCl3)δ:9.92(s,1H),8.63(d,1H),8.46(d,1H),7.85(d,1H), 7.70-7.64(m,6H),7.41(d,1H),7.19-7.11(m,5H),7.04(dd,1H),6.92(d,2H),3.81(s,3H).
Embodiment 4
The preparation method of N- (4- chlorphenyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -4:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- (4- chlorphenyl) -4- Chloro-2-Pyridyle formamide 8-4:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with 4- chloroaniline 7-4 (1.28g, 10mmol), white solid 2.00g, yield 75% is made.
1H NMR(400MHz,CDCl3)δ:9.93(s,1H),8.53(d,1H),8.30(d,1H),7.73(d,2H),7.51 (dd,1H),7.37(d,2H).
The system of step 5 N- (4- chlorphenyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -4 It is standby:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- (4- chlorobenzene Base) -4- Chloro-2-Pyridyle formamide 8-4 (267mg, 1mmol) be raw material, be made white solid 277mg, yield 65%.
1H NMR(400MHz,CDCl3)δ:10.05(s,1H),8.64(d,1H),8.48(d,1H),7.85(d,1H), 7.74-7.66(m,6H),7.43-7.34(m,3H),7.19-7.07(m,6H).
Embodiment 5
The preparation method of N- isopropyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -5:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- isopropyl -4- Chloro-2-Pyridyle formamide 8-5:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with isopropylamine 7-5 (0.59g, 10mmol), yellow solid 1.43g, yield 72% is made.
1H NMR(400MHz,CDCl3)δ:8.43(d,1H),8.19(d,1H),7.80(s,1H),7.41(dd,1H), 4.30-4.22(m,1H),1.28(d,6H).
The preparation of step 5 N- isopropyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -5:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- isopropyl -4- Chloro-2-Pyridyle formamide 8-5 (199mg, 1mmol) is raw material, and brown solid 197mg, yield 55% is made.
1H NMR(400MHz,CDCl3)δ:8.61(d,1H),8.39(d,1H),7.87(d,1H),7.76(d,1H), 7.68-7.61(m,4H),7.38(d,1H),7.16-7.08(m,5H),6.98(dd,1H),4.28-4.20(m,1H),1.27 (d,6H).
Embodiment 6
The preparation method of N- cyclopropyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -6:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- cyclopropyl -4- Chloro-2-Pyridyle formamide 8-6:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with cyclopropylamine 7-6 (0.57g, 10mmol), yellow solid 1.49g, yield 76% is made.
1H NMR(400MHz,CDCl3)δ:8.40(d,1H),8.19(d,1H),7.98(s,1H),7.42(dd,1H), 2.96-2.91(m,1H),0.88(m,2H),0.66(m,2H).
The preparation of step 5 N- cyclopropyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -6:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- cyclopropyl -4- Chloro-2-Pyridyle formamide 8-6 (197mg, 1mmol) is raw material, and brown solid 217mg, yield 61% is made.
1H NMR(400MHz,CDCl3)δ:8.72(d,1H),8.58(d,1H),8.48(d,1H),7.77-7.70(m, 4H),7.52-7.50(m,2H),7.31-7.18(m,4H),7.14-7.11(m,2H),2.93-2.86(m,1H),0.67(d, 4H).
Embodiment 7
The preparation method of N- cyclohexyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -7:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- cyclohexyl -4- Chloro-2-Pyridyle formamide 8-7:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with cyclohexylamine 7-7 (0.99g, 10mmol), pink solid 1.72g, yield 72% is made.
1H NMR(400MHz,CDCl3)δ:8.43(d,1H),8.20(d,1H),7.87(s,1H),7.41(dd,1H), 4.00-3.92(m,1H),2.03-1.98(m,2H),1.78-1.74(m,2H),1.68-1.63(m,1H),1.48-1.38(m, 2H),1.36-1.22(m,3H).
The preparation of step 5 N- cyclohexyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -7:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- cyclohexyl -4- Chloro-2-Pyridyle formamide 8-7 (239mg, 1mmol) is raw material, and yellow solid 239mg, yield 60% is made.
1H NMR(400MHz,CDCl3)δ:8.58(d,1H),8.52(d,1H),8.42(d,1H),7.78-7.70(m, 4H),7.54-7.48(m,2H),1H),7.33-7.11(m,6H),3.77-3.73(m,1H),1.78-1.52(m,5H),1.41- 1.06(m,5H).
Embodiment 8
The preparation method of N- benzyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -8:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- benzyl -4- Chloro-2-Pyridyle formamide 8-8:
According to 1 step 4 of embodiment, methylamine 7-1 (0.31g, 10mmol) is replaced with into benzylamine 7-8 (1.07g, 10mmol), Yellow solid 1.75g, yield 71% is made.
1H NMR(400MHz,CDCl3)δ:8.44(d,1H),8.32(s,1H),8.27(d,1H),7.45(dd,1H), 7.38-7.30(m,5H),4.69(d,2H).
The preparation of step 5 N- benzyl -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -8:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- benzyl -4- Chloro-2-Pyridyle formamide 8-8 (247mg, 1mmol) is raw material, and brown solid 240mg, yield 59% is made.
1H NMR(400MHz,CDCl3)δ:8.62(d,1H),8.41-8.37(m,2H),7.80(d,1H),7.68-7.62 (m,4H),7.40-7.28(m,6H),7.17-7.09(m,5H),7.00(dd,1H),4.64(d,2H).
Embodiment 9
The preparation method of N- (4- luorobenzyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -9:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- (4- luorobenzyl) -4- Chloro-2-Pyridyle formamide 8-9:
According to 1 step 4 of embodiment, by methylamine 7-1 (0.31g, 10mmol) replace with 4- fluorin benzyl amine 7-9 (1.25g, 10mmol), yellow solid 1.99g, yield 75% is made.
1H NMR(400MHz,CDCl3)δ:8.45(d,1H),8.29-8.25(m,2H),7.46(dd,1H),7.36-7.33 (m,2H),7.07-7.03(m,2H),4.65(d,2H).
The system of step 5 N- (4- luorobenzyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -9 It is standby:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- (4- fluorine benzyl Base) -4- Chloro-2-Pyridyle formamide 8-9 (265mg, 1mmol) be raw material, be made white solid 289mg, yield 68%.
1H NMR(400MHz,CDCl3)δ:8.60(d,1H),8.43-8.36(m,2H),7.78(d,1H),7.67-7.60 (m,4H),7.38(d,1H),7.32-7.28(m,2H),7.16-7.07(m,5H),7.02-6.98(m,3H),4.59(d,2H).
Embodiment 10
The preparation of N- (4- methoxy-benzyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -10 Method:
The preparation of step 1 2- (4- nitrostyrolene base) pyridine 3:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 1 of embodiment.
The preparation of step 2 2- (4- aminostyryl) pyridine 4:
2- (4- aminostyryl) pyridine is synthesized according to 1 step 2 of embodiment.
The preparation of step 3 4- chloropyridine -2- acyl chlorides 6:
4- chloropyridine -2- acyl chlorides is synthesized according to 1 step 3 of embodiment.
The preparation of step 4 N- (4- methoxy-benzyl) -4- Chloro-2-Pyridyle formamide 8-10:
According to 1 step 4 of embodiment, methylamine 7-1 (0.31g, 10mmol) is replaced with into 4- methoxybenzylamine 7-10 Yellow solid 2.05g, yield 74% is made in (1.37g, 10mmol).
1H NMR(400MHz,CDCl3)δ:8.40(d,1H),8.17(d,1H),7.98(s,1H),7.39(dd,1H), 3.01(d,3H).
Step 5 N- (4- methoxy-benzyl) -4- (4- (2- (2- pyridyl group) vinyl) anilino-) pyridine carboxamide I -10 Preparation:
According to 1 step 5 of embodiment, with 2- (4- aminostyryl) pyridine 4 (196mg, 1mmol) and N- (4- methoxyl group Benzyl) -4- Chloro-2-Pyridyle formamide 8-10 (276mg, 1mmol) be raw material, be made faint yellow solid 275mg, yield 63%.
1H NMR(400MHz,CDCl3)δ:8.60(d,1H),8.36-8.33(m,2H),7.78(d,1H),7.66-7.59 (m,4H),7.36(d,1H),7.26(d,2H),7.14-7.06(m,5H),6.96(dd,1H),6.84(d,2H),4.55(d, 2H),3.75(s,3H).
1 compound number of table and corresponding structural formula
Embodiment 11
The external inhibitory activity test measurement of the tumour cell of the compounds of this invention:
Using the inhibitory activity of non-small cell lung cancer A549 and hepatocellular carcinoma H22 verifying compound, Sorafenib is selected For control drug.A549 and HepG2 cell is inoculated in 96 orifice plates respectively, after 37 DEG C of incubator cultures for 24 hours, it is 50 that concentration, which is added, μM untested compound, continue cultivate 48h after, handled with PBS buffer solution, be added CCK-8 solution, continue cultivate 2h, microplate reader Detect OD value.The inhibiting rate of different compound on intracellular proliferation is calculated, concrete outcome is shown in Table 2.
The inhibitory activity of 2. compound on tumor cell of table
From upper table 2 as it can be seen that the compounds of this invention shows good anti tumor activity in vitro, the antitumor work of part of compounds Property be better than positive control drug Sorafenib, compound is especially apparent the inhibitory activity of non-small cell lung cancer A549.Wherein, change It closes I -1, I -6 and I -9 couple of non-small cell lung cancer A549 of object and hepatocellular carcinoma H22 all has higher inhibitory activity, with the positive Comparison medicine Sorafenib is suitable or more excellent.For example, the suppression of chemical compounds I -6 couples of non-small cell lung cancer A549 and hepatocellular carcinoma H22 Rate processed is respectively 78.18% and 75.97%, is above positive control drug Sorafenib.

Claims (10)

1. a kind of pyridine structure contained styrylpyridinium compound, which is characterized in that the pyridine structure contained styryl Pyridine compounds have logical structure shown in formula I
2. as described in claim 1 with general formula I pyridine structure contained styrylpyridinium compound preparation method include with Lower step:
Step 1: every preparation one unit 2- (4- nitrostyrolene base) pyridine (3) uses following steps:
10mmol 2- picoline (1), 10mmol 4- hydroxy benzaldehyde (2) are mixed into 20mmol acetic anhydride and 2mmol acetic acid It is added in single port bottle, accesses anhydrous calcium chloride drying tube, be heated to vigorous reflux, continue back flow reaction about for 24 hours, TLC monitoring is anti- It should finish, be concentrated under reduced pressure, the dissolution of 30mL methylene chloride is added in residue, and reaction solution successively uses 20% sodium bicarbonate aqueous solution and steaming Distilled water washing, anhydrous sodium sulfate dry, filter, and are concentrated under reduced pressure, and ethyl alcohol recrystallization obtains yellow solid 2.04g, yield 90%；
Step 2: every preparation one unit 2- (4- aminostyryl) pyridine (4) uses following steps:
9mmol 2- (4- nitrostyrolene base) pyridine (3) is dissolved in 20mL ethyl alcohol, the ammonium chloride that 20mL 4mol/L is added is molten Liquid adds 40mmol iron powder, is heated to 50 DEG C, and TLC monitors end of reaction, filtering, and filtrate is concentrated, and ethyl acetate extracts repeatedly It takes, organic phase anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains yellow solid 1.53g, yield 86%；
Step 3: one unit 4- chloropyridine -2- acyl chlorides (6) of every preparation uses following steps:
0.1mL anhydrous DMF and 20mL thionyl chloride are added in single port bottle, nitrogen protection is passed through, is heated to 50 DEG C, reaction Then 10min is added portionwise 60mmol 2- pyridine carboxylic acid (5), is heated to flowing back, continue back flow reaction about 17h, and TLC monitoring is anti- It should finish, 20mL dilution with toluene is added, be concentrated under reduced pressure, repeat the operation twice, obtain brown oil 10.28g, yield 97%；
Step 4: one unit 4- Chloro-2-Pyridyle Carbox amide (8) of every preparation uses following steps: 10mmol is organic Aminated compounds (7) is dissolved in 15mL methylene chloride, and temperature is controlled at 0 DEG C or so, and 10mmol 4- chloropyridine -2- acyl chlorides (6) is molten It in 15mL methylene chloride, is slowly added dropwise into organic amine compound (7) solution, reacts about 3h at room temperature, TLC monitoring has been reacted Finish, reaction solution saturated common salt water washing, anhydrous sodium sulfate dries, filters, and it is chloro- to obtain 4- for recrystallization from ethyl acetate/petroleum ether 2- pyridine carboxamides (8)；
Step 5: the pyridine structure contained styrylpyridinium compound (I) of one unit of every preparation uses following steps: by 1mmol 2- (4- aminostyryl) pyridine (4) and 1mmol 4- Chloro-2-Pyridyle Carbox amide (8) are dissolved in 20mL acetonitrile, 1mmol zinc nitrate is added, is passed through nitrogen protection, is heated to flowing back, keeps thermotonus, TLC monitors end of reaction, depressurizes dense The dilution of 30mL ethyl acetate is added in contracting, and reaction solution saturated common salt water washing, anhydrous sodium sulfate dries, filters, and ethyl acetate/ Petroleum ether recrystallization, obtains pyridine structure contained styrylpyridinium compound (I).
3. as claimed in claim 1 or 2 with the pyridine structure contained styrylpyridinium compound and its preparation side of general formula I Method, it is characterised in that: the R is selected from unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, alkyl.
4. there is the pyridine structure contained styrylpyridinium compound and preparation method thereof of general formula I as claimed in claim 3, It is characterized by: the unsubstituted aryl is phenyl.
5. there is the pyridine structure contained styrylpyridinium compound and preparation method thereof of general formula I as claimed in claim 3, It is characterized by: the substituted aryl is the phenyl replaced selected from following group, comprising: halogen, alkoxy.
6. there is the pyridine structure contained styrylpyridinium compound and preparation method thereof of general formula I as claimed in claim 3, It is characterized by: the unsubstituted benzyl is benzyl.
7. there is the pyridine structure contained styrylpyridinium compound and preparation method thereof of general formula I as claimed in claim 3, It is characterized by: the substituted benzyl is the benzyl replaced selected from following group, comprising: alkoxy, halogen.
8. there is the pyridine structure contained styrylpyridinium compound and preparation method thereof of general formula I as claimed in claim 3, It is characterized by: the alkyl is selected from methyl, isopropyl, cyclopropyl, cyclohexyl.
9. the pyridine structure contained styrylpyridinium compound with general formula I is preparing antineoplastic as described in claim 1 The application of object.
10. application according to claim 9, it is characterized in that: the anti-tumor drug be suitable for liver cancer, kidney, lung cancer, The anti-tumor drug of thyroid cancer, colon cancer.
CN201910583916.7A 2019-07-01 2019-07-01 A kind of pyridine structure contained styrylpyridinium compound, preparation method and its application for preparing anti-tumor drug Pending CN110172037A (en)

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Application publication date: 20190827