CN105669565A - Isolongifolanone pyrimidine compound, and preparation method and application thereof - Google Patents

Isolongifolanone pyrimidine compound, and preparation method and application thereof Download PDF

Info

Publication number
CN105669565A
CN105669565A CN201610162124.9A CN201610162124A CN105669565A CN 105669565 A CN105669565 A CN 105669565A CN 201610162124 A CN201610162124 A CN 201610162124A CN 105669565 A CN105669565 A CN 105669565A
Authority
CN
China
Prior art keywords
isolonglifolane
isolongifolanone
tert
compound
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610162124.9A
Other languages
Chinese (zh)
Other versions
CN105669565B (en
Inventor
王石发
芮坚
徐徐
杨益琴
徐海军
匡洪波
王芸芸
谷文
饶卫东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yangzhou Shengning Information Technology Co ltd
Original Assignee
Nanjing Forestry University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Forestry University filed Critical Nanjing Forestry University
Priority to CN201610162124.9A priority Critical patent/CN105669565B/en
Publication of CN105669565A publication Critical patent/CN105669565A/en
Application granted granted Critical
Publication of CN105669565B publication Critical patent/CN105669565B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems

Abstract

The invention discloses an isolongifolanone pyrimidine compound, and a preparation method and application thereof. The preparation method includes compounding isolongifolanone, serving as a raw material, with tertiary butanol, serving as a solvent and a catalyst, through condensation, cyclization and the like to obtain six isolongifolanone pyrimidine compounds. The isolongifolanone pyrimidine compound has the advantages that derivates, namely isolongifolanone, of renewable resource longifolene serve as the raw material of the novel isolongifolanone pyrimidine compound, and a good inhabitation effect on lung cancer cells is achieved; a certain theoretical basis is provided for design of novel nitrogen heterocyclic compounds and analysis of structure-function relationships; domestic channels for deep processing and comprehensive utilization of turpentine are increased.

Description

Isolonglifolane yl pyrimidines compounds and preparation method thereof and application
Technical field
The invention belongs to Minute Organic Synthesis technology and technical field of medicine synthesis, relate to isolonglifolane yl pyrimidines compounds, be specifically related to isolonglifolane yl pyrimidines compounds and preparation method thereof and the application of anti-hepatocarcinoma.
Background technology
Pyrimidines is widely present in nature, and such as sulfadiazine, barbital, vitamin B1 etc., in vital movement, pyrimidines plays huge effect, is the main component of genetic code. Pyrimidines agriculturally can as insecticide, antibacterial, herbicide etc., due to it efficiently, low toxicity, wide spectrum and model of action unique, it has also become a very active field in pesticides discovery research. At field of medicaments, pyrimidines is concentrated mainly on antitumor and two aspects of antiviral, and including highly important anti-hepatic-B virus medicine and inverase, in treatment Other diseases, pyrimidines also has excellent behavior. At agriculture field, evil demodicid mite class is all showed greater activity in the compound fenazaquin of 20th century the eighties tail period by Dow company of the U.S., it is 2.8mg/L and 2.3mg/L to two-spotted spider mite ovum and 24 hours LC50 of active demodicid mite, citrus trees, apple tree red spider are also had good prevention effect, lasting period length and to natural enemies security. Pees etc. are found that 2-(cyano group) pyrimidines that part 5-phenyl replaces has good sterilization or bacteriostatic activity, wherein venturia inaequalis is had the bactericidal effect of 100%, rice blast fungus is also had 75%～89% preventive effect (consumption is 200mg/L). The sulfonylurea herbicide sulfone flazasulfuron developed by du pont company is the acetolactate synthestase by suppressing plant, stops the biosynthesis of branched-chain amino acid, thus suppressing cell division. Grass family and broad leaved weed that plant separate living tissue is sensitive after sulfone flazasulfuron processes stop growing, and then chlorisis, speckle are withered, until Herb is dead. At field of medicaments, terazosin hydrochloride can reduce peripheral vascular resistance, is used for treating benign prostate hyperplasia and hypertension; Nimustine can be used for treating cerebroma, pulmonary carcinoma, gastric cancer, colon cancer, the esophageal carcinoma, malignant lymphoma and leukemia etc.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, it is an object of the invention to provide isolonglifolane yl pyrimidines compounds, meets drug use demand.The preparation method that it is a further object of the present invention to provide a kind of above-mentioned isolonglifolane yl pyrimidines compounds, with isolongitolanone for raw material, has synthesized isolonglifolane yl pyrimidines compounds. Further object of the present invention is to provide the application of a kind of above-mentioned isolonglifolane yl pyrimidines compounds.
Technical scheme: for achieving the above object, the technical solution used in the present invention is:
Isolonglifolane yl pyrimidines compounds, structural formula is:
In formula: Ar be rubigan, to fluorophenyl, p-methylphenyl, p-methoxyphenyl, phenyl, to dimethylamino phenyl.
Concrete title and the structural formula of isolonglifolane yl pyrimidines compounds 3a～3f are as follows:
Compound 3a:4-(4'-chlorphenyl)-6,6,10,10-tetramethyl-6,7,8,9,10,10-hexahydro-5H-6,9-methylene bridge benzo-2-quinazoline amine, structural formula is as follows:
Compound 3b:4-(4'-fluorophenyl)-6,6,10,10-tetramethyl-6,7,8,9,10,10-hexahydro-5H-6,9-methylene bridge benzo-2-quinazoline amine, structural formula is as follows:
Compound 3c:6,6,10,10-tetramethyl-4-p-methylphenyl-6,7,8,9,10,10-hexahydro-5H-6,9-methylene bridge benzo-2-quinazoline amine, its structural formula is as follows:
Compound 3d:4-(4'-methoxyphenyl)-6,6,10,10-tetramethyl-6,7,8,9,10,10-hexahydro-5H-6,9-methylene bridge benzo-2-quinazoline amine, its structural formula is as follows:
Compound 3e:6,6,10,10-tetramethyl-4-phenyl-6,7,8,9,10,10-hexahydro-5H-6,9-methylene bridge benzo-2-quinazoline amine, its structural formula is as follows:
Compound 3f:4-(4'-dimethylamino phenyl)-6,6,10,10-tetramethyl-6,7,8,9,10,10-hexahydro-5H-methylene bridge benzo-2-quinazoline amine, its structural formula is as follows:
The synthetic method of isolonglifolane yl pyrimidines compounds, step is as follows:
1) adopting isolongitolanone 1 is initiation material, with potassium tert-butoxide as catalyst, carries out aldol condensation with aromatic aldehyde, obtains to 7-aryl methylene isolonglifolane ketone compounds (2a～2f), and concrete reaction equation is:
2) with 7-aryl methylene isolongitolanone (2a～2f) of synthesis under the effect of base catalyst, carry out cyclization with guanidine hydrochloride, prepare novel isolonglifolane base-2-amino-metadiazine compound (3a～3f).
The concrete synthetic method of 7-aryl methylene isolonglifolane ketone compounds is: be sequentially added in the 500mL there-necked flask being furnished with agitator, thermometer and reflux condenser by 22g isolongitolanone, tert-butyl alcohol 300mL, 2.8g potassium tert-butoxide and 0.1mol aromatic aldehyde, stirring, back flow reaction about 1～5h reaches more than 95% to isolongitolanone conversion ratio. After the reactant liquor decompression Distillation recovery tert-butyl alcohol, adding distilled water and be extracted with ethyl acetate 3 times, the organic facies distilled water of merging and saturated common salt are washed to neutrality, through anhydrous Na2SO4Dry, filter, obtain yellow liquid crude product after concentration, then dissolve with ethanol, put into refrigerator, recrystallization after cooling, obtain 7-aryl methylene isolonglifolane ketone compounds 2a～2f.
The concrete synthetic method of isolonglifolane base pyrazole compound is: in being furnished with thermometer, reflux condenser, 50mL there-necked flask, it is sequentially added into 7-aryl methylene isolonglifolane ketone compounds, guanidine hydrochloride and the tert-butyl alcohol, add a certain amount of catalyst after being stirred and heated to uniform temperature to react, after reaction terminates, the recovered under reduced pressure tert-butyl alcohol, residue adds a certain amount of acetic acid ethyl dissolution, it is washed with distilled water to neutrality, again with saturated common salt water washing once, dry with anhydrous sodium sulfate again, after reclaiming ethyl acetate, obtain crude product.Crude product carries out recrystallization through Ethanol-Acetic Acid dicyandiamide solution, obtains isolonglifolane base pyrazole compound (3a～3f).
The application in preparing cancer therapy drug of the isolonglifolane yl pyrimidines compounds.
Described cancerous cell is hepatoma carcinoma cell.
Beneficial effect: compared with prior art, advantages of the present invention has: 1) utilize the derivant isolongitolanone of Renewable resource longifolene to prepare novel isolonglifolane yl pyrimidines compounds for raw material, it is provided that a kind of method synthesizing isolonglifolane base class pyrimidines. 2) hepatoma carcinoma cell (HepG2) is had good inhibiting effect by isolonglifolane yl pyrimidines compounds. 3) for the analysis of design novel azaheterocyclic compound and structure activity relationship, it is provided that certain theoretical foundation, the terebinthine deep processing of China and comprehensive utilization channel are expanded.
Detailed description of the invention
Below in conjunction with being embodied as case, this invention is further illustrated.
Embodiment 1
1) preparation of 7-aryl methylene isolonglifolane ketone compounds (2a～2f):
Logical method: 22g isolongitolanone, tert-butyl alcohol 300mL, 2.8g potassium tert-butoxide and 0.1mol aromatic aldehyde are sequentially added in the 500mL there-necked flask being furnished with agitator, thermometer and reflux condenser, stirring, back flow reaction about 1～5h reaches more than 95% to isolongitolanone conversion ratio. After the reactant liquor decompression Distillation recovery tert-butyl alcohol, add distilled water and be extracted with ethyl acetate 3 times, the organic facies distilled water and the saturated common salt that merge are washed to neutrality, dry through anhydrous Na 2SO4, filter, concentrate after obtain yellow liquid crude product, dissolve with ethanol again, put into refrigerator, recrystallization after cooling, obtain 7-aryl methylene isolonglifolane ketone compounds 2a～2f.
2) preparation of isolonglifolane base pyrazole compound (3a～3f):
Logical method: in being furnished with thermometer, reflux condenser, 50-mL there-necked flask, it is sequentially added into 7-aryl methylene isolonglifolane ketone compounds (5mmol), guanidine hydrochloride (20mmol) and the tert-butyl alcohol (60mL), add catalyst (5mmol) after being stirred and heated to uniform temperature to react, after reaction terminates, the recovered under reduced pressure tert-butyl alcohol, residue adds a certain amount of acetic acid ethyl dissolution, it is washed with distilled water to neutrality, again with saturated common salt water washing once, dry with anhydrous sodium sulfate again, after reclaiming ethyl acetate, obtain crude product. Crude product carries out recrystallization through Ethanol-Acetic Acid dicyandiamide solution, obtains isolonglifolane base pyrazole compound (3a～3f).
Compound (3a) product characterizes: white flock crystal, and yield is 87.8%, and productivity is 64.0%, m.p.235.6～236.2 DEG C; IR (KBr) ν: 3505,3317,3195 (νN-H, NH2), 2964 (νasC-H, CH3), 2869 (νsC-H, CH3), 1622 (νC=N), 1549 (δN-H, NH2), 1491,1456 (νC=C, phenyl ring C=C ring stretching vibration), 1369 (νC-N), 1207,1087 (τC-H, phenyl ring C-H in-plane bending vibration), 834 (τC-H, to disubstituted benzenes ring C-H out-of-plane bending vibration);1HNMR (600MHz, DMSO-d6) δ ppm:0.59 (s, 3H), 0.75 (s, 3H), 0.94 (s, 3H), 1.09～1.10 (m, 1H), 1.18 (d, J=9.8Hz, 1H), 1.32 (s, 3H), 1.46～1.52 (m, 1H), 1.58～1.64 (m, 1H), 1.71 (d, J=3.7Hz, 1H), 1.78 (d, J=9.7Hz, 1H), 1.82～1.86 (m, 1H), 2.00 (d, J=15.7Hz, 1H), 2.19 (s, 1H), 2.79 (d, J=15.7Hz, 1H), 6.18 (s, 2H, NH2), 7.51 (d, J=8.5Hz, 2H), 7.58 (d, J=8.5Hz, 2H);13CNMR (150MHz, CDCl3) δ ppm:22.92,24.78,25.43,25.88,28.38,30.11,32.70,37.25,39.47,44.42,48.01,55.29,57.94,116.14,128.40,130.34,134.93,137.05,160.20,164.93,170.09; MS (70eV) m/z (%): 382 (M+, 31), 381 (97), 380 (18), 366 (19), 352 (33), 326 (13), 299 (100), 282 (10), 258 (17), 232 (5), 207 (5), 179 (2), 147 (6), 115 (5), 91 (6), 55 (8).
Compound (3b) product characterizes: colourless transparent crystal, is 86.5%, and yield is 62.5%, m.p.228.7～229.4 DEG C; IR (KBr) ν: 3486,3272,3149 (νN-H, NH2), 2957 (νasC-H, CH3), 2872 (νsC-H, CH3), 1616 (νC=N), 1554 (δN-H, NH2), 1511,1454 (νC=C, phenyl ring C=C ring stretching vibration), 1378 (νC-N), 1226 (τC-H, phenyl ring C-H in-plane bending vibration), 844 (τC-H, to disubstituted benzenes ring C-H out-of-plane bending vibration);1HNMR (600MHz, DMSO-d6) δ ppm:0.59 (s, 3H), 0.75 (s, 3H), 0.94 (s, 3H), 1.09～1.10 (m, 1H), 1.19 (d, J=9.5Hz, 1H), 1.32 (s, 3H), 1.46～1.51 (m, 1H), 1.58～1.64 (m, 1H), 1.71 (d, J=3.0Hz, 1H), 1.78 (d, J=9.7Hz, 1H), 1.82～1.86 (m, 1H), 2.01 (d, J=15.7Hz, 1H), 2.19 (s, 1H), 2.80 (d, J=15.7Hz, 1H), 6.15 (s, 2H, NH2), 7.25～7.29 (m, 2H), 7.60～7.62 (m, 2H);13CNMR (150MHz, CDCl3) δ ppm:22.93,24.80,25.45,25.88,28.38,30.15,32.72,37.28,39.58,44.42,48.07,55.34,58.01,115.17,116.11,130.87,134.78,160.28,162.27,163.92,165.13,170.02; MS (70eV) m/z (%): 365 (M+, 100), 364 (18), 350 (18), 336 (32), 310 (11), 283 (97), 266 (11), 242 (15), 216 (5), 198 (2), 159 (3), 115 (3), 91 (5), 55 (6).
Compound (3c) product characterizes: colourless transparent crystal, and yield is 88.2%, and yield is 53.2%, m.p.207.1～208.0 DEG C; IR (KBr) ν: 3507,3314,3197 (νN-H, NH2), 2963 (νasC-H, CH3), 2868 (νsC-H, CH3), 1623 (νC=N), 1550 (δN-H, NH2), 1457 (νC=C, phenyl ring C=C ring stretching vibration), 1374 (νC-N), 1206,1177 (τC-H, phenyl ring C-H in-plane bending vibration), 818 (τC-H, to disubstituted benzenes ring C-H out-of-plane bending vibration);1HNMR (600MHz, DMSO-d6) δ ppm:0.58 (s, 3H, ), 0.75 (s, 3H), 0.93 (s, 3H), 1.09～1.10 (m, 1H), 1.18 (d, J=9.6Hz, 1H), 1.32 (s, 3H), 1.46～1.52 (m, 1H), 1.58～1.63 (m, 1H), 1.71 (d, J=3.5Hz, 1H), 1.78 (d, J=9.7Hz, 1H), 1.82～1.86 (m, 1H), 2.04 (d, J=15.7Hz, 1H), 2.18 (s, 1H), 2.36 (s, 3H), 2.78 (d, J=15.7Hz, 1H), 6.09 (s, 2H, NH2), 7.25 (d, J=7.9Hz, 2H), 7.44 (d, J=7.9Hz, 2H);13CNMR (150MHz, CDCl3) δ ppm:21.37,22.88,24.79,25.41,25.87,28.41,30.12,32.68,37.23,39.53,44.34,48.02,55.33,57.96,116.10,128.81,135.88,138.72,160.30,166.20,169.62;MS (70eV) m/z (%): 361 (M+, 100), 346 (22), 332 (31), 306 (11), 279 (97), 262 (10), 238 (14), 212 (4), 194 (2), 165 (2), 147 (4), 118 (6), 91 (9), 55 (6).
Compound (3d) product characterizes: white flock crystal, and yield is 87.4%, and yield is 55.7%, m.p.202.7～203.3 DEG C; IR (KBr) ν: 3500,3424,3306,3184 (νN-H, NH2), 2958 (νas C-H, CH3), 2874 (νsC-H, CH3), 1608 (νC=N), 1550 (δN-H, NH2), 1512,1460 (νC=C, phenyl ring C=C ring stretching vibration), 1367 (νC-N), 1246 (ν asC-O-C), 1174 (τC-H, phenyl ring C-H in-plane bending vibration), 1032 (ν sC-O-C), 838 (τC-H, to disubstituted benzenes ring C-H out-of-plane bending vibration);1HNMR (600MHz, DMSO-d6) δ ppm:58 (s, 3H), 0.75 (s, 3H), 0.94 (s, 3H), 1.07～1.11 (m, 1H), 1.19 (d, J=9.8Hz, 1H), 1.32 (s, 3H), 1.46～1.51 (m, 1H), 1.58～1.63 (m, 1H), 1.71 (d, J=4.0Hz, 1H), 1.79 (d, J=9.8Hz, 1H), 1.82～1.86 (m, 1H), 2.07 (d, J=15.7Hz, 1H), 2.17 (s, 1H), 2.81 (d, J=15.7Hz, 1H), 3.81 (s, 3H, OCH3), 6.07 (s, 2H, NH2), 6.99 (d, J=8.8Hz, 2H), 7.53 (d, J=8.8Hz, 2H);13CNMR (150MHz, CDCl3) δ ppm:22.87,24.79,25.45,25.84,28.40,30.10,32.70,37.22,39.72,44.36,48.02,55.33,57.96,113.49,115.97,130.48,131.05,160.15,165.67,169.59; MS (70eV) m/z (%): 377 (M+, 100), 362 (19), 348 (32), 298 (98), 278 (8), 254 (15), 228 (4), 207 (3), 170 (2), 145 (5), 115 (4), 91 (6), 55 (7).
Compound (3e) product characterizes: the crystal of white flock, and yield is 85.9%, and yield is 42.1%, m.p.241.2～241.9 DEG C; IR (KBr) ν: 3490,3276,3152 (νN-H, NH2), 2959 (νasC-H, CH3), 2938 (νasC-H, CH2), 2872 (νsC-H, CH3), 1615 (νC=N), 1553 (δN-H, NH2), 1457 (νC=C, phenyl ring C=C ring stretching vibration), 1376 (νC-N), 1207 (τC-H, phenyl ring C-H in-plane bending vibration), 765,700 (τC-H, monosubstituted phenyl ring C-H out-of-plane bending vibration);1HNMR (600MHz, DMSO-d6) δ ppm:0.59 (s, 3H), 0.76 (s, 3H), 0.93 (s, 3H), 1.08～1.10 (m, 1H), 1.19 (d, J=9.7Hz, 1H), 1.33 (s, 3H), 1.45～1.51 (m, 1H), 1.58～1.64 (m, 1H), 1.72 (d, J=3.7Hz, 1H), 1.78 (d, J=9.4Hz, 1H), 1.82～1.86 (m, 1H), 2.03 (d, J=15.7Hz, 1H), 2.19 (s, 1H), 2.78 (d, J=15.7Hz, 1H), 6.12 (s, 2H, NH2), 7.42～7.46 (m, 3H), 7.52～7.54 (m, 2H);13CNMR (150MHz, CDCl3) δ ppm:22.87,24.77,25.37,25.84,28.35,30.12,32.63,37.22,39.39,44.33,48.03,55.33,57.96,116.10,128.09,128.67,128.77,138.80,160.33,166.20,169.74; MS (70eV) m/z (%): 347 (M+, 100), 322 (18), 318 (31), 292 (11), 278 (30), 265 (91), 248 (10), 224 (13), 198 (4), 147 (4), 115 (8), 77 (8), 55 (4).
Compound (3f) product characterizes: brown bulk crystals, and yield is 84.2%, and yield is 57.2%, m.p.211.3～211.9 DEG C; IR (KBr) ν: 3487,3274,3147 (νN-H, NH2), 2957 (νasC-H, CH3), 2872 (νsC-H, CH3), 1608 (νC=N), 1547 (δN-H, NH2), 1453 (νC=C, phenyl ring C=C ring stretching vibration), 1364 (νC-N), 1195,944 (τC-H, phenyl ring C-H in-plane bending vibration), 819 (τC-H, monosubstituted phenyl ring C-H out-of-plane bending vibration;1HNMR (600MHz, DMSO-d6) δ ppm:0.57 (s, 3H), 0.75 (s, 3H), 0.95 (s, 3H), 1.08～1.10 (m, 1H), 1.19 (d, J=9.6Hz, 1H), 1.32 (s, 3H), 1.45～1.51 (m, 1H), 1.58～1.63 (m, 1H), 1.71 (d, J=3.4Hz, 1H), 1.78 (d, J=9.1Hz, 1H), 1.82～1.86 (m, 1H), 2.14 (d, J=12.9Hz, 2H), 2.82 (d, J=15.6Hz, 1H), 2.96 (s, 6H, N (CH3)2), 5.95 (s, 2H, NH2), 6.74 (d, J=8.8Hz, 2H), 7.47 (d, J=8.8Hz, 2H);13CNMR (150MHz, CDCl3) δ ppm:22.83,24.83,25.50,25.83,28.41,30.15,32.74,37.24,40.24,40.34,44.34,48.09,55.36,58.05,111.44,115.79,126.38,130.35,150.83,160.32,166.06,169.20; MS (70eV) m/z (%): 390 (M+, 100), 375 (19), 361 (23), 347 (12), 321 (20), 309 (18), 308 (73), 307 (24), 293 (12), 267 (13), 147 (12), 77 (4), 55 (7).
The physical property of 6 prepared novel isolonglifolane yl pyrimidines compounds is as shown in table 1
The physical property of table 1 compound 3a～3f
Embodiment 2
Isolonglifolane yl pyrimidines compounds 3a～3f anti-tumor activity test to hepatocarcinoma (HepG2).
1) with DMEM culture medium culturing hepatoma carcinoma cell (HepG2) containing 10% calf serum, cell is placed on CO2Incubator is cultivated (37 DEG C, 5%CO2, 95% air, keep certain humidity), cell is put under microscope so that observation of cell growing state, according to the growing state of cell, by changing liquid; After cultivating 24～48h, cell can grow into monolayer, then uses 0.25% trypsinization, goes down to posterity by 1:2. Experimentation adopts the hepatoma carcinoma cell (HepG2) growing into monolayer.
2) preparation of drug solution
Target compound DMSO is configured to certain density mother solution, then by RPMI-1640 culture medium, derivant mother solution is diluted to the diluent of different activity gradient, concentration respectively 1 μM, 10 μMs, 100 μMs, 1000 μMs. Remove old culture medium, add the pastille culture medium of variable concentrations, every hole 200 μ L. Separately set blank group and positive control etoposide matched group. After medicine effect 24h, inhale and abandon pastille culture medium, add serum-free in every hole, without phenol red 1640 culture medium 100 μ L.
3) MTT colorimetry anti-tumor activity test
It is that 5mg/mL tetrazolium bromide (MTT) solution joins in ELISA Plate hole by 10 μ L concentration, hatch 4h for 37 DEG C, supernatant is removed after centrifugal, it is separately added into 150 μ L solution, the DMSO solution of tumor cell is vibrated 10 minutes, treating that solid crystal dissolves completely, measure the absorbance of solution, wherein the wavelength X of enzyme connection instrument sets 490nm. Utilize the absorbance value (OD value) in each hole, calculate the proliferation inhibition rate of cell:
I (%)=(1-OD1/OD) × 100%
Wherein, the suppression ratio of I=tumor cell;OD1=dosing group tumor cell absorbance (parallel test is averaged for three times), OD=blank group tumor cell absorbance (parallel test is averaged for three times).
Finally the proliferation inhibition rate of gained is converted into IC50Value (concentration of inducing cell apoptosis 50%).
The IC of table 2 hepatoma carcinoma cell50Value
IC from the hepatoma carcinoma cell of table 250Value is it can be seen that compound 3a shows good active anticancer, IC50Value is 8.581 ± 0.5 μMs, its IC compared with existing anti-liver cancer drug50Value is closer to, and simultaneously that human body Human umbilical vein endothelial cells toxicity is less, hepatoma carcinoma cell is had certain inhibitory action by compound 3b, 3d, 3f, can be seen that-Cl >-N (CH from this experiment3)2>-F>-OCH3>-CH3>-H, illustrate that the inhibitory action of HepG2 is existed bigger difference by different functional groups.

Claims (6)

1. isolonglifolane yl pyrimidines compounds, the general structure of this compound is:
In formula: Ar be rubigan, to fluorophenyl, p-methylphenyl, p-methoxyphenyl, phenyl, to dimethylamino phenyl.
2. the synthetic method of the isolonglifolane yl pyrimidines compounds described in claim 1, it is characterised in that comprise the technical steps that:
1) adopting isolongitolanone is initiation material, with potassium tert-butoxide as catalyst, carries out aldol condensation with aromatic aldehyde, obtains to 7-aryl methylene isolonglifolane ketone compounds;
2) with the 7-aryl methylene isolongitolanone of synthesis for raw material, under the effect of base catalyst, carry out cyclization with guanidine hydrochloride, prepare novel isolonglifolane base-2-amino-metadiazine compound.
3. the synthetic method of isolonglifolane yl pyrimidines compounds according to claim 2, it is characterized in that, step 1) particularly as follows: 22g isolongitolanone, tert-butyl alcohol 300mL, 2.8g potassium tert-butoxide and 0.1mol aromatic aldehyde are sequentially added in the 500mL there-necked flask being furnished with agitator, thermometer and reflux condenser, stirring, back flow reaction about 1～5h reaches more than 95% to isolongitolanone conversion ratio; After the reactant liquor decompression Distillation recovery tert-butyl alcohol, adding distilled water and be extracted with ethyl acetate 3 times, the organic facies distilled water of merging and saturated common salt are washed to neutrality, through anhydrous Na2SO4Dry, filter, obtain yellow liquid crude product after concentration, then dissolve with ethanol, put into refrigerator, recrystallization after cooling, obtain 7-aryl methylene isolonglifolane ketone compounds.
4. the synthetic method of isolonglifolane yl pyrimidines compounds according to claim 2, it is characterized in that, step 1) particularly as follows: be furnished with thermometer, reflux condenser, in 50-mL there-necked flask, it is sequentially added into 7-aryl methylene isolonglifolane ketone compounds 5mmol, guanidine hydrochloride 20mmol and tert-butyl alcohol 60mL, add catalyst 5mmol after stirring and heating to react, after reaction terminates, the recovered under reduced pressure tert-butyl alcohol, residue adds acetic acid ethyl dissolution, it is washed with distilled water to neutrality, again with saturated common salt water washing once, dry with anhydrous sodium sulfate again, crude product is obtained after reclaiming ethyl acetate, crude product carries out recrystallization through Ethanol-Acetic Acid dicyandiamide solution, obtains isolonglifolane base pyrazole compound.
5. the application in preparing cancer therapy drug of the isolonglifolane yl pyrimidines compounds described in claim 1.
6. application according to claim 5, it is characterised in that described cancerous cell is hepatoma carcinoma cell.
CN201610162124.9A 2016-03-21 2016-03-21 Isolonglifolane yl pyrimidines class compound and preparation method and application Active CN105669565B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610162124.9A CN105669565B (en) 2016-03-21 2016-03-21 Isolonglifolane yl pyrimidines class compound and preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610162124.9A CN105669565B (en) 2016-03-21 2016-03-21 Isolonglifolane yl pyrimidines class compound and preparation method and application

Publications (2)

Publication Number Publication Date
CN105669565A true CN105669565A (en) 2016-06-15
CN105669565B CN105669565B (en) 2017-07-11

Family

ID=56311264

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610162124.9A Active CN105669565B (en) 2016-03-21 2016-03-21 Isolonglifolane yl pyrimidines class compound and preparation method and application

Country Status (1)

Country Link
CN (1) CN105669565B (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588772A (en) * 2016-12-19 2017-04-26 广西中医药大学 Heavy turpentine longifolene derivative, preparation thereof and application
CN106632239A (en) * 2016-10-10 2017-05-10 南京林业大学 Isolongifolanone based hexahydroquinazoline-2-amine Schiff base type fluorescent material, and synthetic method and application thereof
CN106632084A (en) * 2016-10-10 2017-05-10 南京林业大学 Iso-longitolanone based hexahydroquinazoline-2-amine Schiff base Zn<2+> fluorescent probe as well as preparation method and application thereof
CN107434801A (en) * 2017-03-27 2017-12-05 南京林业大学 A kind of 4 ' pyridyl-pyrimidine class compounds and its synthetic method and application
CN107459488A (en) * 2017-09-04 2017-12-12 南京林业大学 Isolonglifolane base and the amine Schiff bases fluorescent chemicals of pyrimidine 2 and preparation method thereof
CN107892654A (en) * 2017-11-30 2018-04-10 南京林业大学 A kind of isolonglifolane base fluorescent type acid-base indicator and its synthetic method and application
CN108424393A (en) * 2018-03-13 2018-08-21 南京林业大学 A kind of hypochlorous acid fluorescence probe and its preparation method and application
CN108586361A (en) * 2018-04-03 2018-09-28 南京林业大学 Isolonglifolane base dihydro-pyrimidin thioketone and its preparation method and application
CN109761917A (en) * 2019-02-15 2019-05-17 南京林业大学 Isolonglifolane ketone group -2- Aminopyrimidines boron trifluoride fluorescence probe and its synthetic method and application
CN110551070A (en) * 2018-05-30 2019-12-10 南京林业大学 Synthesis of camphoryl pyrimidine compounds and antitumor activity thereof
CN111892539A (en) * 2020-08-03 2020-11-06 南京林业大学 Isolongifolenone caprolactam derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102076676A (en) * 2008-07-01 2011-05-25 奇华顿股份有限公司 Isolongifolanyl-derivatives suitable as odorants
US20120277325A1 (en) * 2011-02-15 2012-11-01 Belko Robert P Novel pyrimidine derivatives and their use in perfume compositions
CN103360324A (en) * 2012-03-27 2013-10-23 国际香料和香精公司 Novel pyrimidine derivatives and their use in perfume compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102076676A (en) * 2008-07-01 2011-05-25 奇华顿股份有限公司 Isolongifolanyl-derivatives suitable as odorants
US20120277325A1 (en) * 2011-02-15 2012-11-01 Belko Robert P Novel pyrimidine derivatives and their use in perfume compositions
CN103360324A (en) * 2012-03-27 2013-10-23 国际香料和香精公司 Novel pyrimidine derivatives and their use in perfume compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
魏松柏: "（+）-2-羟基-3-蒎酮合成新型手性含氮杂环化合物及抗菌活性研究", 《南京林业大学研究生硕士学位论文》 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632084B (en) * 2016-10-10 2019-01-04 南京林业大学 Isolonglifolane ketone group hexahydro quinazoline -2- amine Schiff bases zinc ion fluorescent and its preparation method and application
CN106632239A (en) * 2016-10-10 2017-05-10 南京林业大学 Isolongifolanone based hexahydroquinazoline-2-amine Schiff base type fluorescent material, and synthetic method and application thereof
CN106632084A (en) * 2016-10-10 2017-05-10 南京林业大学 Iso-longitolanone based hexahydroquinazoline-2-amine Schiff base Zn<2+> fluorescent probe as well as preparation method and application thereof
CN106632239B (en) * 2016-10-10 2019-04-12 南京林业大学 A kind of isolonglifolane ketone group hexahydro quinazoline -2- amine schiff's base type fluorescent material and its synthetic method and application
CN106588772A (en) * 2016-12-19 2017-04-26 广西中医药大学 Heavy turpentine longifolene derivative, preparation thereof and application
CN106588772B (en) * 2016-12-19 2020-04-24 广西中医药大学 Heavy turpentine longifolene derivative and preparation and application thereof
CN107434801A (en) * 2017-03-27 2017-12-05 南京林业大学 A kind of 4 ' pyridyl-pyrimidine class compounds and its synthetic method and application
CN107459488A (en) * 2017-09-04 2017-12-12 南京林业大学 Isolonglifolane base and the amine Schiff bases fluorescent chemicals of pyrimidine 2 and preparation method thereof
CN107459488B (en) * 2017-09-04 2019-05-07 南京林业大学 Isolonglifolane base and pyrimidine -2- amine Schiff bases fluorescent chemicals and preparation method thereof
CN107892654B (en) * 2017-11-30 2020-02-14 南京林业大学 Isolongifolane-based fluorescent acid-base indicator and synthetic method and application thereof
CN107892654A (en) * 2017-11-30 2018-04-10 南京林业大学 A kind of isolonglifolane base fluorescent type acid-base indicator and its synthetic method and application
CN108424393A (en) * 2018-03-13 2018-08-21 南京林业大学 A kind of hypochlorous acid fluorescence probe and its preparation method and application
CN108586361A (en) * 2018-04-03 2018-09-28 南京林业大学 Isolonglifolane base dihydro-pyrimidin thioketone and its preparation method and application
CN110551070A (en) * 2018-05-30 2019-12-10 南京林业大学 Synthesis of camphoryl pyrimidine compounds and antitumor activity thereof
CN109761917A (en) * 2019-02-15 2019-05-17 南京林业大学 Isolonglifolane ketone group -2- Aminopyrimidines boron trifluoride fluorescence probe and its synthetic method and application
CN109761917B (en) * 2019-02-15 2022-02-08 南京林业大学 Isolongifolanone-2-aminopyrimidine boron trifluoride fluorescent probe and synthetic method and application thereof
CN111892539A (en) * 2020-08-03 2020-11-06 南京林业大学 Isolongifolenone caprolactam derivative and preparation method and application thereof

Also Published As

Publication number Publication date
CN105669565B (en) 2017-07-11

Similar Documents

Publication Publication Date Title
CN105669565A (en) Isolongifolanone pyrimidine compound, and preparation method and application thereof
CN102206172B (en) Substituted diaryl compound and preparation method and antiviral application thereof
CN105175410A (en) Triazine compound and preparing method and antineoplastic application thereof
CN108610348A (en) A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent
CN103965118B (en) One class pinane base-2-amino-metadiazine compound and synthetic method thereof and application
CN107417628A (en) Diaryl quianzolinones, its preparation method and its medical usage and the pharmaceutical composition comprising such compound
CN102260260B (en) 8-phenyl xanthine compound, preparation method, medicine composition including the compound and purpose thereof
CN104230905A (en) Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs
CN112106779A (en) Application of A-ring modified cryptolepine derivative in prevention and treatment of agricultural plant diseases
CN101638391B (en) 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative and preparation method and application thereof
CN106673988A (en) Benzyl cyclohexenone derivative and preparation method and medical application thereof
CN103922992B (en) A kind of antitumour activity indolone derivatives, preparation method and use
CN104530056A (en) Heterozygote of adjacent naphthoquinone and tetrazol-pyrimidine and synthetic method thereof
CN110437156A (en) Paeonol dihydro-pyrimidin ketones derivant and its preparation method and application
CN102173997A (en) Liver cancer, gastric cancer and cervical cancer-resistant archen derivative and preparation method thereof
CN104945388A (en) Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs
CN104230915A (en) Thiazolidinedione-containing phenylpiperazine derivatives as well as preparation method and applications of thiazolidinedione-containing phenylpiperazine derivatives
CN102268003B (en) Unsymmetrical poly-substituted porphyrin gold (III) type anticancer compound and preparation method thereof
CN103804303B (en) Epidermal growth factor receptor (EGFR) small-molecule inhibitor pyrimidine derivative as well as preparation method and use thereof
CN102942552A (en) 3,11-disubstituted-14-aryl-14H-dibenzo[a,j]xanthene derivatives, preparation methods and uses thereof
CN108299433B (en) Substituted phenanthrene compounds with spiro structures and preparation method and application thereof
CN106317030A (en) 4-indolyl coumarin derivative, and preparing method and application thereof
CN104530062B (en) A kind of 1,4-naphthoquinone derivatives and synthetic method thereof
CN103059001B (en) Quinazolinone Schiff base containing triazole and preparation method thereof
CN104230786B (en) Indole-structure-containing compound with anti-tumor activity and synthesis method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20181220

Address after: 225002 Chen Ci Village, Shatou Town, Guangling District, Yangzhou City, Jiangsu Province

Patentee after: YANGZHOU YIYANG TECHNOLOGY DEVELOPMENT Co.,Ltd.

Address before: No. 159, dragon pan Road, Xuanwu District, Nanjing, Jiangsu

Patentee before: Nanjing Forestry University

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20220829

Address after: 225000 Lidian town science and Technology Pioneer Park, Guangling District, Yangzhou City, Jiangsu Province

Patentee after: Yangzhou Shengning Information Technology Co.,Ltd.

Address before: 225002 Chen Ci Village, Shatou Town, Guangling District, Yangzhou City, Jiangsu Province

Patentee before: YANGZHOU YIYANG TECHNOLOGY DEVELOPMENT Co.,Ltd.