CN103965118A - Pinanyl-2-aminopyrimidine compounds as well as synthesis method and application thereof - Google Patents
Pinanyl-2-aminopyrimidine compounds as well as synthesis method and application thereof Download PDFInfo
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- CN103965118A CN103965118A CN201410226625.XA CN201410226625A CN103965118A CN 103965118 A CN103965118 A CN 103965118A CN 201410226625 A CN201410226625 A CN 201410226625A CN 103965118 A CN103965118 A CN 103965118A
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- 0 CC1C(C)(C)C(C)c2nc(N)nc(-c3ccc(*)cc3)c2C1 Chemical compound CC1C(C)(C)C(C)c2nc(N)nc(-c3ccc(*)cc3)c2C1 0.000 description 1
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses pinanyl-2-aminopyrimidine compounds as well as a synthesis method and application thereof. The synthesis method comprises the following steps: by taking beta-pinene as a raw material, selectively oxidizing to obtain (+)-nopinone; carrying out aldol condensation with aromatic aldehyde to obtain 3-aryl methylene nopinone; then, carrying out cyclization reaction with guanidine hydrochloride to obtain the pinanyl-2-aminopyrimidine compounds. According to the invention, the pinanyl-2-aminopyrimidine compounds are synthesized by special space structures so as to screen the compounds with effective antineoplastic activity by using the main component beta-pinene in the most abundant natural extract turpentine in China, so that the source of antineoplastic drugs is expanded, and the compounds are of significance to the field of utilization of turpentine in China. The isopinanyl-2-aminopyrimidine compounds have good antineoplastic activity to human breast cancer cell MCF-7, human lung cancer cell A549 and human hepatoma carcinoma cells HepG2 and SMMC-7721.
Description
Technical field
The invention belongs to organic compound technical field, be specifically related to class pinane base-2-amino-metadiazine compound and synthetic method and an application.
Background technology
The life that the mankind in malignant tumour serious threat is with healthy, the patient that malignant tumour is died from the whole world every year reach millions of more than, account for 1/4th of total death toll.Finding effective cancer therapy drug and method, thoroughly capture cancer, is the important research topic of world medical circle.The selection of anticancer, antitumor medicament, is first that it must have certain resolving ability to target cell, moreover is woven with notable difference with respect to healthy tissues and tumor group.Along with the research of the synthetic anticancer, antitumor medicament of pyrimidines is deep into clinical experimental stage gradually, this compounds shows for different molecular targets bioactive characteristic.
Pyrimidine ring is the heterogeneous ring compound that has hydrophilic and hydrophobic two aspects concurrently, pyrimidines is because having simple in structure and broad-spectrum biological activity (as sterilization, deinsectization, antitumor) etc. feature and occupy very important position widely people's research in agricultural chemicals and medicine initiative.Pyrimidines demonstrates very high biological activity always, people had found again that some medicines that contain pyrimidine ring had antineoplastic activity in recent years, if: 5 FU 5 fluorouracil is widely used and tumour cell is had to inhibiting antitumor activity medicine clinically, mainly apply to the treatment of cancer of the stomach, intestinal cancer, mammary cancer etc., there is good clinical effectiveness.Nitric acid pyrimidine nitrogen mustards antitumor drug, has that anticancer spectrum is wide, selectivity is high, low toxin, and is widely used clinically.The 4-amino-quinazoline compound replacing containing the N-of pyrimidine ring has the restraining effect to EGF-R ELISA (EGFR), and concrete manifestation goes out the effects such as anti-lung cancer, cancer of the stomach, prostate cancer, ovarian cysts and carcinoma of gallbladder.
Beta-pinene in turps is bicyclic terpene compounds, there is specific space structure, natural chiral raw material and the chiral intermediate that a class is abundant, utilize its distinctive three-dimensional arrangement, by synthesizing mean by active group---pyrimidine ring combines with it, develops pinane base-2-amino-metadiazine compound with anti-tumor activity.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, the object of the present invention is to provide class pinane base-2-amino-metadiazine compound, can meet antineoplastic user demand.Another object of the present invention is to provide the synthetic method of above-mentioned pinane base-2-amino-metadiazine compound.The present invention also has an object to be to provide the application of above-mentioned pinane base-2-amino-metadiazine compound.
Technical scheme: in order to realize foregoing invention object, the technical solution adopted in the present invention is:
One class pinane base-2-amino-metadiazine compound, general structure is:
In formula, Ar is p-methylphenyl, phenyl, p-hydroxybenzene, p-methoxyphenyl, to hydroxyl m-methoxyphenyl, rubigan, to fluorophenyl, p-nitrophenyl, m-nitro base or furyl.
Concrete title and structural formula are as follows:
Compound (2a): 5,6,7,8-tetrahydrochysene-4-(4'-aminomethyl phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2b): 5,6,7,8-tetrahydrochysene-4-phenyl-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2c): 5,6,7,8-tetrahydrochysene-4-(4'-hydroxy phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2d): 5,6,7,8-tetrahydrochysene-4-(4'-methoxyl group base phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2e): 5,6,7,8-tetrahydrochysene-4-(4'-hydroxyl-3'-p-methoxy-phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2f): 5,6,7,8-tetrahydrochysene-4-(4'-chloro-phenyl-)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2g): 5,6,7,8-tetrahydrochysene-4-(4'-fluorophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2h): 5,6,7,8-tetrahydrochysene-4-(4'-nitrophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2i): 5,6,7,8-tetrahydrochysene-4-(3'-nitrophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
Compound (2j): 5,6,7,8-tetrahydrochysene-4-(2'-furyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine,
The synthetic method of one class pinane base-2-amino-metadiazine compound: first taking (-)-beta-pinene as raw material, obtain (+)-nopinone through selective oxidation; Carry out aldol condensation with aromatic aldehyde again, obtain 3-aryl methylene nopinone; Then carry out cyclization with Guanidinium hydrochloride, obtain pinane base-2-amino-metadiazine compound.Concrete reaction formula is:
Described pinane base-2-amino-metadiazine compound is in the application for the preparation of in inhibition tumor cell medicine.
Described tumour cell comprises: human breast cancer cell MCF-7, human lung cancer cell A549, human liver cancer cell HepG2 and SMMC-7721.
Beneficial effect: compared with prior art, the present invention adopts the main component beta-pinene in the natural extract turps that China enriches the most, utilize its specific space structure synthesizing pinane base-2-amino-metadiazine compound, screening has the compound of highly effective antineoplastic activity.Expand the source of antitumor drug, also significant to expanding the terebinthine field that utilizes of China.This different pinane base-2-amino-metadiazine compound has good anti-tumor activity to human breast cancer cell MCF-7, human lung cancer cell A549, human liver cancer cell HepG2 and SMMC-7721.
Brief description of the drawings
Fig. 1 is cell scratch experiment result figure.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described.
The preparation of embodiment 1 nopinone
In the present embodiment, the preparation of nopinone, in reference literature [research of the synthetic dextrorotation nopinone of left-handed beta-pinene selective oxidation, Nanjing Forestry University's journal (natural science edition), 2010,02:89-94], disclosed method is carried out.Prepared nopinone is colourless oil liquid, productive rate 84%, and purity 95.3% (GC),
The preparation of embodiment 23-aryl methylene nopinone compounds (1a～1f)
1) 3-benzylidene nopinone (1a) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, 30mL distilled water, 6.00g NaOH and 1.27g phenyl aldehyde, be heated to back flow reaction 8h left and right to nopinone transformation efficiency and reach more than 95% (GC follows the tracks of detection) under induction stirring.After cooling, in reaction solution, add saturated aqueous common salt and be extracted with ethyl acetate (20mL × 3) 3 times, the organic phase of merging is washed to neutrality with saturated common salt, through anhydrous Na
2sO
4after being dried, filtering, concentrating, obtain yellow solid crude product, then use acetone even with a small amount of dissolve with ethanol, standing crystallization, obtains 1.77g colourless transparent crystal, and productive rate is 78.2%, and purity is 98.2% (GC), m.p.108.4～108.9 DEG C,
2) 3-(4'-methyl benzylidene) nopinone (1b) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, the 30mL trimethyl carbinol, 3.00g sodium methylate and 1.44g p-tolyl aldehyde, under induction stirring, be heated to back flow reaction 2～3h, nopinone transformation efficiency reaches more than 95% (GC tracking monitor).Aftertreatment is with reference to 1), colourless transparent crystal, productive rate is 85.7%, purity is 98.3% (GC), m.p.95.2～95.8 DEG C,
3) 3-(2'-chlorine benzylidene) nopinone (1c) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, 30mL methyl alcohol, 1.62g sodium methylate and 1.68g o-chlorobenzaldehyde, under induction stirring, heating reflux reaction 1h reaches 100% to nopinone transformation efficiency.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate is 90.9%, purity is 99.0% (GC), m.p.109.7～110.7 DEG C,
4) 3-(4'-hydroxyl benzylidene) nopinone (1d) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, the 30mL trimethyl carbinol, 3.00g potassium tert.-butoxide and 1.83g p-Hydroxybenzaldehyde, be heated to back flow reaction 7～8h and reach more than 95% (GC follows the tracks of detection) to nopinone transformation efficiency under induction stirring.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate is 69.3%, purity is 98.5% (GC), m.p.199.6～200.6 DEG C,
5) 3-(4'-methoxyl group benzylidene) nopinone (1e) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, the 30mL trimethyl carbinol, 3.00g potassium tert.-butoxide and 2.04g aubepine, under induction stirring, heating reflux reaction 1～2.5h reaches 100% (GC follows the tracks of detection) to nopinone transformation efficiency.Aftertreatment is with reference to 1), colourless transparent crystal, yield is 83.5%, purity is 98.1% (GC), m.p.82.7～83.8 DEG C,
6) 3-(furans-2'-methylene radical) nopinone (1f) is synthetic
In the 100mL there-necked flask of being furnished with thermometer and reflux exchanger, add successively 1.38g nopinone, 30mL ethanol, 3.00g NaOH and 1.15g furfural, under induction stirring, heating reflux reaction 4～4.5h reaches more than 95% (GC follows the tracks of detection) to nopinone transformation efficiency.After cooling, in reaction solution, add saturated aqueous common salt and be extracted with ethyl acetate (20mL × 3) 3 times, organic phase water and the saturated common salt of merging are washed to neutrality, through anhydrous Na
2sO
4after being dried, filtering, concentrating, obtain yellow liquid crude product, [V after silica gel column chromatography separates
sherwood oil: V
ethyl acetate=6:1], obtain 1.85g yellow liquid, yield is 85.5%, GC purity 97.1%,
The preparation of embodiment 3 pinane base-2-amino-metadiazine compounds
The precursor skeleton carbon atoms numbered of pinane base-2-amino-metadiazine compound is shown below.
1) 5,6,7,8-tetrahydrochysene-4-(4'-aminomethyl phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.20g compound 1a, 0.96g Guanidinium hydrochloride, 30mL dehydrated alcohol, 1.20g NaOH and 1.20g distilled water, under induction stirring, be heated to reflux temperature reaction 10h left and right to the transformation efficiency of 1a and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.After cooling, in reaction solution, add 30mL deionized water, be extracted with ethyl acetate 3 times (40mL × 3), the organic phase of merging is washed to neutrality with saturated common salt, through anhydrous Na
2sO
4dry, filter, obtain yellow thick liquid crude product after concentrated, then use glacial acetic acid and anhydrous alcohol solution even, leave standstill crystallization, obtain 2.50g colourless transparent crystal 2a, productive rate 89.6%, purity is 98.7% (GC), m.p.106.7～107.3 DEG C,
fT-IR (KBr) v/cm
-1: 3316,3187 (v
n-H, NH
2), 2923 (v
asC-H, CH
3), 2859 (v
asC-H, CH
2), 1701 (v
c=N), 1625 (δ
n-H, NH
2), 1560,1512 (v
c=C), 1458 (δ
asC-H, CH
3), 1376 (δ
sC-H, CH
3), 1274,1215 (v
c -C), 1065 (v
c-N), 823,800,603,575;
1hNMR (500MHz, CDCl
3) δ: 0.78 (s, 3H, 10-CH
3), 1.32 (d, J=9.8Hz, 1H, 6-CH), 1.41 (s, 3H, 11-CH
3), 2.32 (t, J=2.8Hz, 1H, 8-CH), 2.42 (s, 3H, Ar-CH
3) 2.66～2.83 (m, 4H, 9,5-CH
2), 6.27 (s, 2H, NH
2), 7.28 (t, J=1.2Hz, 2H, 3', 5'-CH), 7.47 (d, J=8.1Hz, 2H, 2', 6'-CH);
13cNMR (500MHz, CDCl
3) δ: 21.24,21.36,25.76,29.28,29.78,38.80,40.24,48.97,113.58,128.30,128.99,134.50,139.21,160.37,164.35,176.20; EI-MS (70ev) m/z (%): 279 (M
+, 55), 264 (33), 236 (45), 119 (100), 91 (16), 77 (15).
2) 5,6,7,8-tetrahydrochysene-4-phenyl-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.13g compound 1b, 0.96g Guanidinium hydrochloride, 30mL dehydrated alcohol, 1.20g NaOH and 1.20g distilled water, under induction stirring, be heated to reflux temperature reaction 12h left and right to the transformation efficiency of 1b and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate 90.1%, purity is 98.2% (GC), m.p.98.8～99.5 DEG C,
fT-IR (KBr) v/cm
-1: 3320,3191 (v
n-H, NH
2), 2971 (v
asC-H, CH
3), 2946 (v
asC-H, CH
2), 2934 (v
sC-H, CH
3), 2866 (v
sC-H, CH
2), 1704 (v
c=N), 1625 (δ
n-H, NH
2), 1566,1552 (v
c=C), 1465 (δ
asC-H, CH
3), 1379 (δ
sC-H, CH
3), 1271,1216 (v
c-C), 1071 (v
c-N), 774,700;
1hNMR (500MHz, CDCl
3) δ: 0.78 (s, 3H, 10-CH
3), 1.31 (d, J=9.8Hz, 1H, 6-CH), 1.40 (s, 3H, 11-CH
3), 2.30 (m, 1H, 9 α-CH), 2.63～2.68 (m, 1H, 9 β-CH
2), 2.74 (t, J=2.6Hz, 2H, 5-CH
2), 2.82 (t, J=5.5Hz, 1H, 8-CH), 6.59 (s, 2H, NH
2), 7.43～7.47 (m, 3H, 3', 4', 5'-CH), 7.53 (t, J=2.1Hz, 2H, 2', 6'-CH);
13cNMR (500MHz, CDCl
3) δ: 21.16,25.66,29.00,29.67,38.73,40.09,48.65,113.40,128.18,128.22,129.12,137.02,160.31,164.44,176.16; EI-MS (70ev) m/z (%): 265 (M
+, 52), 250 (29), 222 (48), 119 (100), 77 (28), 51 (7).
3) 5,6,7,8-tetrahydrochysene-4-(4'-hydroxy phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.21g compound 1c, 0.96g Guanidinium hydrochloride, 30mL toluene, 5mL ethanol and 2.24g potassium tert.-butoxide, under induction stirring, be heated to reflux temperature reaction 10h left and right to the transformation efficiency of 1c and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate 80.3%, purity is 98.3% (GC), m.p.272.4～273.1 DEG C,
fT-IR (KBr) v/cm
-1: 3488 (vO-H), 3294,3165 (v
n-H, NH
2), 2970 (v
asC-H, CH
3), 2946 (v
asC-H, CH
2), 2928 (v
sC -H, CH
3), 2866 (v
sC-H, CH
2), 1627 (v
c=N), 1610 (δ
n-H, NH
2), 1556,1514 (v
c=C), 1467 (δ
asC-H, CH
3), 1445 (δ
sC-H, CH
3), 1380 (v
c-O), 1279 (v
c-C), 1230 (v
c-N), 842,800;
1hNMR (300MHz, DMSO) δ: 0.68 (s, 3H, 10-CH
3), 1.23 (d, J=8.6Hz, 1H, 6-CH), 1.35 (s, 3H, 11-CH
3), 2.30 (t, J=2.6Hz, 1H, 8-CH), 2.50～2.64 (m, 2H, 9-CH
2), 2.71～2.88 (m, 2H, 5-CH
2), 6.19 (s, 2H, NH
2), 6.83 (d, J=8.6Hz, 2H, 3', 5'-CH), 7.57 (d, J=8.6Hz, 2H, 2', 6'-CH), 9.67 (s, 1H, Ar-OH);
13cNMR (300MHz, CDCl
3) δ: 21.54,26.11,29.82,29.89,38.61,40.87,50.07,111.82,115.20,129.92,130.51,158.41,161.76,162.65,175.56; EI-MS (70ev) m/z (%): 281 (M
+, 75), 266 (40), 238 (53), 119 (100), 77 (17).
4) 5,6,7,8-tetrahydrochysene-4-(4'-methoxyl group base phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.28g compound 1d, 0.96g Guanidinium hydrochloride, 30mL ethanol, 1.20g NaOH and 1.20g distilled water, under induction stirring, be heated to reflux temperature reaction 12h left and right to the transformation efficiency of 1d and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate 73.4%, purity is 99.0% (GC), m.p.175.5～176.1 DEG C,
fT-IR (KBr) v/cm
-1: 3311,3186 (v
n -H, NH
2), 2949 (v
asC-H, CH
3), 2936 (v
asC-H, CH
2), 2866 (v
sC-H, CH
3), 2837 (v
sC-H, CH
2), 1735 (v
c=N), 1609 (δ
n-H, NH
2), 1581,1560 (v
c=C), 1512 (v
asC-O-C), 1458 (δ
asC-H, CH
3), 1374 (δ
sC-H, CH
3), 1250 (v
sC-O-C), 1196,1174 (v
c-C), 1037 (v
c-O), 834,801,580;
1hNMR (500MHz, CDCl
3) δ: 0.75 (s, 3H, 10-CH
3), 1.32 (d, J=9.7Hz, 1H, 6-CH), 1.38 (s, 3H, 11-CH
3), 2.32 (m, 1H, 9 α-CH), 2.63 (m, 1H, 9 β-CH), 2.75 (t, J=5.5Hz, 1H, 8-CH), 2.84 (m, 2H, 5-CH
2), 3.84 (s, 3H, Ar-OCH
3), 5.19 (s, 2H, NH
2), phenyl: 6.96 (m, 2H, 3', 5'-CH), 7.60 (m, 2H, 2', 6'-CH);
13cNMR (500MHz, CDCl
3) δ: 21.21,25.79,29.58,29.89,38.71,40.41,50.29,55.27,113.60,113.76,129.88,131.00,160.06,160.79,163.16,176.43; EI-MS (70ev) m/z (%): 295 (M
+, 74), 280 (40), 252 (49), 119 (100), 77 (14).
5) 5,6,7,8-tetrahydrochysene-4-(4'-hydroxyl-3'-p-methoxy-phenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.36g compound 1e, 0.96g Guanidinium hydrochloride, 30mL toluene, 5mL ethanol and 2.24g potassium tert.-butoxide, under induction stirring, be heated to reflux temperature reaction 13h left and right to the transformation efficiency of 1e and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment reference compound 2a, colourless transparent crystal, productive rate 62.1%, purity is 98.8% (GC), m.p.222.8～223.5 DEG C,
fT-IR (KBr) v/cm
-1: 3465 (v
o-H), 3310,3184 (v
n-H, NH
2), 2973 (v
asC-H, CH
3), 2933 (v
asC-H, CH
2), 2914 (v
sC-H, CH
3), 2866 (v
sC-H, CH
2), 1637 (v
c=N), 1608 (δ
n-H, NH
2), 1566,1514 (v
c=C), 1458 (δ
asC-H, CH
3), 1419 (δ
sC-H, CH
3), 1370 (v
c-O), 1270 (v
sC-O-C), 1200,1170 (v
c-C), 1029 (v
c-O), 806,778;
1hNMR (300MHz, DMSO) δ: 0.77 (s, 3H, 10-CH
3), 1.33 (d, J=9.7Hz, 1H, 6-CH), 1.39 (s, 3H, 11-CH
3), 2.34 (t, J=2.8Hz, 1H, 8-CH), 2.61～2.90 (m, 4H, 9,5-CH
2), 3.92 (s, 3H, Ar-OCH
3), 5.98 (s, 2H, NH
2), 6.92～6.95 (d, J=8.0Hz, 1H, 3'-CH), 7.13～7.26 (m, 2H, 2', 6'-CH), 9.19 (s, 1H, Ar-OH);
13cNMR (300MHz, DMSO) δ: 21.20,25.72,29.63,29.78,38.74,40.30,49.29,55.96,111.49,113.52,114.08,122.05,129.56,146.59,160.30,163.57,175.79,176.35; EI-MS (70ev) m/z (%): 311 (M
+, 100), 296 (54), 268 (71), 119 (93), 77 (15).
6) 5,6,7,8-tetrahydrochysene-4-(4'-chloro-phenyl-)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.30g compound 1f, 0.96g Guanidinium hydrochloride, 30mL ethanol, 1.20g NaOH and 1.20g distilled water, under induction stirring, be heated to reflux temperature reaction 9h left and right to the transformation efficiency of 1f and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate 90.2%, purity is 99.4% (GC), m.p.111.8～112.1 DEG C,
fT-IR (KBr) v/cm
-1: 3316,3191 (v
n -H, NH
2), 2968 (v
asC-H, CH
3), 2949 (v
asC-H, CH
2), 2922 (v
sC-H, CH
3), 2869 (v
sC-H, CH
2), 1701 (v
c=N), 1624 (δ
n-H, NH
2), 1578,1560 (v
c=C), 1490 (δ
asC-H, CH
3), 1458 (δ
sC-H, CH
3), 1269 (v
c-
c), 1089 (v
c-
n), 1014,833,800;
1hNMR (500MHz, CDCl
3) δ: 0.76 (s, 3H, 10-CH
3), 1.31 (d, J=9.8Hz, 1H, 6-CH), 1.40 (s, 3H, 11-CH
3), 2.32 (m, 1H, 9 α-CH), 2.66 (m, 1H, 9 β-CH), 2.75 (t, J=3.2Hz, 2H, 5-CH
2), 2.81 (t, J=5.5Hz, 1H, 8-CH), 6.06 (s, 2H, NH
2), 7.42 (m, 2H, 3', 5'-CH), 7.52 (m, 2H, 2', 6'-CH);
13cNMR (500MHz, CDCl
3) δ: 21.24,25.73,29.18,29.77,38.80,40.19,49.20,113.65,128.56,129.78,135.23,136.06,160.52,162.99,175.95; EI-MS (70ev) m/z (%): 299 (M
+, 41), 284 (25), 256 (37), 119 (100), 77 (13).
7) 5,6,7,8-tetrahydrochysene-4-(4'-fluorophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.21g compound 1g, 0.96g Guanidinium hydrochloride, 30mL ethanol, 1.20g NaOH and 1.20g distilled water, under induction stirring, be heated to reflux temperature reaction 16h left and right to the transformation efficiency of 1g and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), colourless transparent crystal, productive rate 57.9%, purity is 99.2% (GC), m.p.182.4～183.0 DEG C,
fT-IR (KBr) v/cm
-1: 3324,3189 (v
n -H, NH
2), 2994 (v
asC-H, CH
3), 2971 (v
asC-H, CH
2), 2936 (v
sC-H, CH
3), 2869 (v
sC-H, CH
2), 1705 (v
c=N), 1644 (δ
n-H, NH
2), 1602,1572 (v
c=C), 1510 (δ
asC-H, CH
3), 1472 (δ
sC-H, CH
3), 1380 (v
c-F), 1271 (v
c-C), 1223 (v
c-N), 845;
1hNMR (300MHz, CDCl
3) δ: 0.78 (
s, 3H, 10-CH
3), 1.33 (d, J=9.8Hz, 1H, 6-CH), 1.41 (s, 3H, 11-CH
3), 2.31～2.35 (m, 1H, 9 α-CH), 2.66～2.70 (m, 1H, 9 β-CH), 2.76 (d, J=2.0Hz, 2H, 5-CH
2), 2.82 (t, J=5.5Hz, 1H, 8-CH), 6.23 (s, 2H, NH
2), 7.11～7.18 (m, 2H, 3', 5'-CH), 7.55～7.59 (m, 2H, 2', 6'-CH);
13cNMR (300MHz, CDCl
3) δ: 21.22,25.72,29.21,29.76,38.79,40.20,49.02,113.55,115.21,115.50,130.42,133.48,160.43,164.84,176.21; EI-MS (70ev) m/z (%): 283 (M
+, 57), 268 (34), 240 (51), 119 (100), 77 (12).
8) 5,6,7,8-tetrahydrochysene-4-(4'-nitrophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.35g compound 1h, 0.96g Guanidinium hydrochloride, the 30mL trimethyl carbinol and 1.68g potassium tert.-butoxide, under induction stirring, normal-temperature reaction 2h left and right to the transformation efficiency of 1h reaches more than 95% (GC follows the tracks of detection), has solid to separate out in reaction process.Aftertreatment is with reference to 1), with ethyl acetate and a small amount of dehydrated alcohol crystallization, obtain yellow transparent crystal, productive rate 57.2%, purity is 99.3% (GC), m.p.253.1～255.0 DEG C,
fT-IR (KBr) v/cm
-1: 3313,3186 (v
n-H, NH
2), 2971 (v
asC-H, CH
3), 2946 (v
asC-H, CH
2), 2921 (v
sC -H, CH
3), 2862 (v
sC-H, CH
2), 1689 (v
c=N), 1625 (δ
n-H, NH
2), 1553 (v
c=C), 1497 (δ
asC-H, CH
3), 1456 (v
asN=O, NO
2), 1380 (δ
sC-H, CH
3), 1217,1198 (v
c -C), 856,801;
1hNMR (300MHz, CDCl
3) δ: 0.77 (s, 3H, 10-CH
3), 1.31 (d, J=9.8Hz, 1H, 6-CH), 1.40 (s, 3H, 11-CH
3), 2.35 (s, 1H, 8-CH), 2.66～2.83 (m, 4H, 9,5-CH
2), 5.15 (s, 2H, NH
2), 7.81 (d, J=8.2Hz, 2H, 3', 5'-CH), 8.28 (d, J=8.2Hz, 2H, 2', 6'-CH);
13cNMR (300MHz, CDCl
3) δ: 21.25,25.73,29.15,29.84,38.81,40.22,50.34,114.37,123.49,129.47,144.77,147.92,160.74,161.15,177.50; EI-MS (70ev) m/z (%): 310 (M
+, 50), 295 (28), 267 (52), 119 (100), 77 (12).
9) 5,6,7,8-tetrahydrochysene-4-(3'-nitrophenyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.35g compound 1i, 0.96g Guanidinium hydrochloride, the 30mL trimethyl carbinol and 1.68g potassium tert.-butoxide, under induction stirring, normal-temperature reaction 2h left and right to the transformation efficiency of 1i reaches more than 95% (GC follows the tracks of detection), has solid to separate out in reaction process.Aftertreatment is with reference to 1), with ethyl acetate and a small amount of dehydrated alcohol crystallization, obtain yellow transparent crystal, productive rate 57.9%, purity is 99.0% (GC), m.p.110.8～111.7 DEG C,
fT-IR (KBr) v/cm
-1: 3322,3188 (v
n-H, NH
2), 2971 (v
asC-H, CH
3), 2946 (v
asC-H, CH
2), 2921 (v
sC -H, CH
3), 2862 (v
sC-H, CH
2), 1706 (v
c=N), 1646 (δ
n-H, NH
2), 1570,1532 (v
c=C), 1468 (v
asN=O, NO
2), 1378 (δ
asC-H, CH
3), 1348 (δ
sC-H, CH
3), 1217,1199 (v
c-C), 716,696;
1hNMR (300MHz, CDCl
3) δ: 0.79 (s, 3H, 10-CH
3), 1.35 (d, J=9.8Hz, 1H, 6-CH), 1.42 (s, 3H, 11-CH
3), 2.35～2.38 (m, 1H, 9 α-CH), 2.66～2.73 (m, 1H, 9 β-CH
2), 2.81 (d, J=2.5Hz, 2H, 5-CH
2), 2.84 (d, J=5.5Hz, 1H, 8-CH), 5.94 (s, 2H, NH
2), 7.63～7.68 (t, J=7.9Hz, 1H, 5'-CH), 7.96 (d, J=7.7Hz, 1H, 4'-CH), 8.31 (d, J=8.2Hz, 1H, 6'-CH), 8.50 (s, 1H, 2'-CH);
13cNMR (300MHz, CDCl
3) δ: 21.28,25.72,29.11,29.77,38.85,40.16,49.40,113.85,123.59,123.83,129.42,134.47,139.48,160.68,161.31,175.85,177.29; EI-MS (70ev) m/z (%): 310 (M
+, 50), 295 (30), 267 (58), 119 (100), 77 (12).
10) 5,6,7,8-tetrahydrochysene-4-(2'-furyl)-7,7-dimethyl-6,8-methylene bridge-2-quinazoline amine synthetic
In the 50mL there-necked flask of being furnished with thermometer and condenser, add successively 1.08g compound 1j, 0.96g Guanidinium hydrochloride, the 30mL trimethyl carbinol and 1.12g potassium tert.-butoxide, under induction stirring, be heated to reflux temperature reaction 14h left and right to the transformation efficiency of 1j and reach more than 95% (GC follows the tracks of detection), in reaction process, have solid to separate out.Aftertreatment is with reference to 1), brown transparent crystals, productive rate 50.2%, purity is 98.2% (GC), m.p.147.8～149.1 DEG C,
fT-IR (KBr) v/cm
-1: 3318,3187 (v
n-H, NH
2), 2971 (v
asC-H, CH
3), 2950 (v
asC-H, CH
2), 2914 (v
sC-H, CH
3), 2866 (v
sC-H, CH
2), 1631 (v
c=N), 1597 (δ
n-H, NH
2), 1564 (v
c=C), 1461 (δ
asC-H, CH
3), 1402 (δ
sC-H, CH
3), 1363 (v
c-O), 1221,1199 (v
c-C), 1070 (v
c-N), 1041,1023,807,797;
1hNMR (300MHz, CDCl
3) δ: 0.74 (
s, 3H, 10-CH
3), 1.32 (d, J=9.7Hz, 1H, 6-CH), 1.40 (s, 3H, 11-CH
3), 2.38～2.42 (m, 1H, 9 α-CH), 2.64～2.67 (m, 1H, 9 β-CH), 2.76 (t, J=5.6Hz, 1H, 8-CH), 2.92～3.09 (m, 2H, 5-CH
2), 5.12 (s, 2H, NH
2), 6.54 (m, 1H, 4'-CH), 7.08 (d, J=3.5Hz, 1H, 5'-CH), 7.61 (t, J=1.1Hz, 1H, 3'-CH);
13cNMR (300MHz, CDCl
3) δ: 21.16,25.84,29.97,29.99,38.85,40.20,50.33,111.76,112.21,113.50,144.11,151.93,152.38,160.48,177.27; EI-MS (70ev) m/z (%): 255 (M
+, 80), 240 (38), 187 (29), 212 (88), 119 (100), 77 (26).
Embodiment 4 suppresses activity test to human breast cancer cell MCF-7
Adopt the inhibition activity of cell scratch experiment assessing compound 2a～2j to human breast cancer cell MCF-7.Wherein MCF-7 cell is provided by Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences.Concrete grammar is as follows: collect MCF-7 logarithmic phase cell, adjust concentration of cell suspension, plant 12 orifice plates, every porocyte number 1～2 × 10
5individual; After kind of plate 12h, treat that cell attachment is complete, be " one " stroke horizontal stroke with rifle head on monolayer cell, PBS washes cell 3 times, the cell under removing stroke; Add the substratum (2%FBS, the DMEM of 1% penicillin and Streptomycin sulphate mixed solution) containing 2% serum of medicine to be measured, make the final concentration of medicine to be measured be respectively 20.0 μ mol/L, 40.0 μ mol/L and 80.0 μ mol/L; Put into 37 DEG C, 5%CO
2after cultivating 24h in incubator, sample, take pictures.Test result is as shown in 1.Result shows: pinane base-2-amino-metadiazine compound has the effect of good inhibition ACF-7 tumor cell migration.
Embodiment 5 suppresses activity test to human lung cancer cell A549
The proliferation inhibition activity of the compound 2a that employing MTT experimental evaluation filters out to human lung cancer cell A549, wherein A549 cell is provided by Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences.Concrete grammar is as follows: collect A549 logarithmic phase cell, adjust concentration of cell suspension and be about 5 × 10
4cell/mL, is inoculated in 96 orifice plates, and every hole 100 μ L, are placed in 37 DEG C, 5%CO
2under condition, hatch that to be paved with hole to cell monolayer low; The mother liquor that tested medicine is mixed with to finite concentration gradient with DMSO, adds substratum, and every hole 100 μ L, separately establish blank group and positive control 5 FU 5 fluorouracil control group; After drug effect 24h, inhale and abandon pastille substratum, add serum-free in every hole, without phenol red 1640 substratum 100 μ L, then add MTT solution (5mg/mL) 10 μ L, continuation incubation 4h; Suck supernatant liquor in each hole, every hole adds DMSO150 μ L, vibration 10min, crystallisate is fully dissolved, microplate reader is measured the absorbance value (OD value) in each hole, 490nm place, calculates the proliferation inhibition rate of cell: inhibiting rate (%)=(the average OD value of the average OD value/blank of 1-medication group group) × 100%; Calculate the half-inhibition concentration (IC of cancer cell multiplication
50): lgIC
50=X
m-I (P-(3-P
m-P
n)/4), wherein, Xm=lg maximal dose, I=lg (maximal dose/adjacent doses), P=positive reaction rate sum, the maximum positive reaction rate of Pm=, the minimum positive reaction rate of Pn=.The results are shown in Table 1.
Table 1 cell light absorption value
| Administration concentration (μ mol/mL) | Control group 0 | 10 | 20 | 40 | 80 |
| Light absorption value OD 570nm | 0.597 | 0.648 | 0.737 | 0.354 | 0.229 |
Result shows: pinane base-2-amino-metadiazine compound 2a (molecular weight 279.38) has good inhibition active to the propagation of A549 cell, IC
50value is 21.60 μ g/mL.
Embodiment 6 suppresses activity test to human liver cancer cell HepG2 and SMMC-7721
Adopt the proliferation inhibition activity of MTT experimental evaluation compound 2a～2j to human liver cancer cell HepG2 and SMMC-7721, wherein HepG2 and SMMC-7721 cell are provided by Nanjing University.Concrete grammar is with reference to the method for embodiment 5.The results are shown in Table 3.
The inhibition activity of table 3 compound 2a～2j to HepG2 and SMMC-7721 cell
As shown in table 3 result, pinane base-2-amino-metadiazine compound of synthesized all has certain inhibited proliferation to different tumour cells, and especially compound 2f all demonstrates stronger inhibition activity, IC to liver cancer cell HepG2 and SMMC-7721
50value is respectively 28.10 μ g/mL and 12.97 μ g/mL.Illustrate that this type of pinane base-2-amino-metadiazine compound shows good antitumour activity, there are the potentiality of exploitation cancer therapy drug.
Claims (4)
1. class pinane base-2-amino-metadiazine compound, is characterized in that, structural formula is as follows:
In formula, Ar is p-methylphenyl, phenyl, p-hydroxybenzene, p-methoxyphenyl, to hydroxyl m-methoxyphenyl, rubigan, to fluorophenyl, p-nitrophenyl, m-nitro base or furyl.
2. the synthetic method of pinane base-2-amino-metadiazine compound claimed in claim 1, is characterized in that: first with (-)-
β-firpene is raw material, obtains (+)-nopinone through selective oxidation; Carry out aldol condensation with aromatic aldehyde again, obtain 3-aryl methylene nopinone; Then carry out cyclization with Guanidinium hydrochloride, obtain novel pinane base-2-amino-metadiazine compound.
3. pinane base-2-amino-metadiazine compound claimed in claim 1 is in the application for the preparation of in inhibition tumor cell medicine.
4. application according to claim 3, is characterized in that: described tumour cell comprises human breast cancer cell MCF-7, human lung cancer cell A549, human liver cancer cell HepG2 and SMMC-7721.
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